Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 1996 by The Gerontological Society of America

1996. Vol.5IA.No. 1, B3-B16

Age-Related Dynamics of Cognitive Brain Functions

in Humans: An Electrophysiological Approach
Christian F. A. Kiigler, Jiirgen Petter, and Dieter Platt

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Institute of Gerontology, University of Erlangen-Niirnberg,
Second Department of Internal Medicine, Nurnberg, Germany.

Event-related P300 potentials closely reflect cognitive functions such as stimulus discrimination (N250) and
processing time (P300 latencies) as well as attention capabilities (P300 amplitudes). To delineate the age-related
dynamics of P300 potentials, we investigated 250 healthy subjects between 18 and 98 years of age in a cross-sectional
study. A total of 330 visual P300 tests was performed in two different paradigms (PI, passive condition, n = 80; PII,
active condition, n = 250). In both P300 paradigms, the N250 and P300 latencies were markedly prolonged (p <
.0001) in older age, whereas the N250 andP300 latency differences between PII and PI did not change (p > .05). The
P300 amplitudes in paradigm I and II revealed only a slight age-related reduction. In fact, the P300 amplitude ratios
between PII and PI remained constant. Third-order polynomial regressions provided the best fit of the aging-P300
interactions in paradigms I and II for both males and females. Interestingly, females showed a greater and possibly
earlier P300 latency increase during aging than males. These age-related changes ofP300 potentials indicate a rather
mild cognitive decline that does not accelerate before old age and may be different between both sexes.

T TNDER normal conditions, early components of evoked
U potentials (EPs) such as the N75 or PI00 of the pattern
reversal visual-evoked potentials are always evoked by ap-
propriate physical stimuli and obviously reflect the process-
ing of their physical qualities in modality-dependent areas of
the central nervous system. In contrast to these exogenous
potentials, event-related P300 potentials are elicited by the
unexpected occurrence (evoked P3) or omission (emitted
P3) of task-relevant stimuli (Sutton et al., 1965; Ruchkin et
al., 1975), that is even without the presence of any physical
stimulus. Therefore, these positive potential peaks occurring
at about 300 msec (P300) after a specific event are referred to
as "endogenous." Although the P300 latencies were found
to be related to stimulus evaluation time for future tasks and
relatively independent of the execution of motor responses
(Kutas et al., 1977; Donchin and Coles, 1988), the negativ-
ity immediately preceding the P300 potential (called N2 or,
as we prefer, N250) proved to be more closely associated
with the immediate control of overt behavior (Duncan-
Johnson and Donchin, 1977). The P300 amplitudes are very
sensitive to both objective overall probability of event occur-
rence and subjective expectancy (Squires et al., 1976;
Duncan-Johnson and Donchin, 1977; Horstetal., 1980) and
closely reflecting subjective task relevance (Wickens et al.,
1983) and attention capabilities (Naatanen, 1975). More-
over, P300 amplitude changes may even predict the proba-
bility of correct remembrance of special stimuli (Fabiani et
al., 1986) or indicate changes of behavioral responses in the
future (Johnson and Donchin, 1982). These data on P300
potentials were interpreted by psychological concepts such
as expectancy (Squires et al., 1976), stimulus evaluation
(Kutas et al., 1977), and context updating (Donchin and
Coles, 1988).
Besides these psychological connotations, P300 poten-
tials clearly are physiological phenomena. Up to now, at
least three different kinds of P300 potentials have been
characterized. The P3b is elicited by task-relevant stimuli
the subjects have to attend to and reveals maximum ampli-
tudes over centroparietal regions. The P3a elicited by unex-
pectedly occurring or emitted task-nonrelevant stimuli
shows a frontocentral amplitude maximum (Squires et al.,
1975). For the novel P3, very complex, task-nonrelevant
stimuli are applied having no similarities with each other. It
occurs especially frontally and rapidly habituates (Cour-
chesne et al., 1975). Topographic analyses of P300 poten-
tials in both humans (Simson et al., 1977; Halgren et al.,
1980; Yingling and Hosobuchi, 1984; Smith et al., 1990)
and animals (Harrison et al., 1988; Pineda et al., 1988)
argue in favor of a widespread ability of various neuronal
networks (e.g., with frontal, parietal, temporal, and hippo-
campal location) to respond to certain events by generating
P300 activity. Moreover, both cholinergic (Hammond et al.,
1987; Meador et al., 1987; Onofrj et al., 1987) and do-
paminergic neurotransmitter systems (Glover et al., 1988;
Noble et al., 1994) seem to be involved in P300 generation,
but the relevance of these findings especially as to other
neurotransmitters (Pinedaetal., 1987; Pritchardetal., 1987;
Ito et al., 1990) still has to be exactly delineated.
From an applied perspective, P300 potentials can be used
in clinical investigations as a neurophysiological variable of
cognitive human brain action, provided that their diagnostic
power has clearly been delineated. One crucial prerequisite
for the clinical utility of P300 potentials, however, is the
exact knowledge of their age-related alterations. Since the
number of elderly subjects afflicted by cognition disorders is
increasing worldwide (Jorm et al., 1987; Henderson, 1993),
a growing body of studies investigated aging effects on P300
potentials to differentiate between physiological and patho-
logical aging of cognitive human brain functions (Kiigler et
al., 1993a, for review). Converging lines of evidence indi-
cate rather mild changes in P300 potentials during aging. By
contrast, there are some controversies about the best fit

B3
B4 KUGLER ET AL.

regression model for the aging-P300 interaction that may
have not only theoretical, but also clinical implications for
the P300 potentials. Furthermore, the influence on the age-
related P300 changes of both gender and specific subjects'
states, such as transient or selective attention, needs further
clarification. In this study, we tried to address these issues by
means of visual event-related P300 potentials elicited in two
different paradigms.
of "transient attention"). In paradigm II (PII), the infre-
quent checkerboard stimuli (64 x 64caskets, 12.5'of visual
angle) were defined as target, and the subjects had to silently
count only these stimuli (active condition of "selective
attention"). The counting error was determined as the mean
difference between the subjects' counts (SC) and the counts
of the computer (CC) of the task-relevant B-stimuli for both
sessions according to the formula:
SC1-CC1 I + ISC2-CC2

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METHODS 1/2 x
CC1 CC2
Subject selection. —Three hundred and thirty visual P300
tests were performed in 250 subjects (103 females and 147 It was significantly greater in elderly subjects (AG III: 4.6%
males) ranging between 18 and 98 years of age. The subjects ± 7.7;AGIV: 13.1% ± 13.1) than in younger ones (AG I:
were recruited from both the community (n = 160) and the 1.9% ± 3.9; AG II: 2.0% ± 2.8; p = .0105; Kruskal-
Department of Internal Medicine (n = 90). Ninety-five Wallis test), but multiple regression analysis did not reveal
percent of them were right-handed, 5% left-handed. Their any effect on P300 parameters (p > .05).
visual acuity, which was determined — if necessary, with In these oddball paradigms, large positive potentials were
glasses — by a conventional sight-testing chart, was regular elicited at about 300 msec after the infrequent B-stimuli (see
(0.9 ± 0.2, mean ± 1 SD). It was well above the critical also Figure 1). The P300 potential was defined as the most
threshold (of about 0.1), which was necessary to clearly see positive peak in the latency range between 270 and 450
the smallest checkerboard patterns (12.5' of visual angle) msec. The N250 was the negative peak immediately preced-
applied for electrophysiological testing. All subjects were in
good general health for their age. Exclusion criteria were
neurologic diseases (e.g., various types of dementias,
Parkinson's disease, multiple sclerosis), long-lasting (more
K.9[M
than 5 years) or complicated diabetes mellitus (e.g., by
, P3
retinopathy), malignancies, cardiac (e.g., heart insuf-
ficiency), pulmonary (e.g., chronic obstructive lung dis-
ease), and renal diseases, especially electrolyte distur-
A
v\
bances. Furthermore, subjects must not take centrally active A V FH.
drugs such as sedatives or tranquilizers. Since the risk for N2
dementia exponentially increases after about age 60 (Jorm et
al., 1987), elderly subjects were especially screened for
organic and metabolic brain syndromes by conventional
laboratory and psychometric tests. They scored normal on P3
the Mini-Mental State Exam (MMSE, 29.8 ± 0.6; Kessler i V
et al., 1988) and cognitive performance test (SKT, 2.0 ±

1
>Sk i, n A

1.8; Erzigkeit, 1989), respectively, and had regular labora-

tory tests. All subjects were informed about the study proce- PU.
dures in detail and gave their informed consent.
For reasons of descriptive data analysis and presentation, A
the subjects were arbitrarily subdivided into four age groups
(AG I: 18-37 yrs, n = 96; AG II: 38-57 yrs, n = 73; AG N2
III: 58-77 yrs, n = 65; and AG IV: 78-98 yrs, n = 16).

Electrophysiological testing. — During electrophysiolo- P3

gical testing, the subjects were sitting in a comfortable
reclining chair 1 m in front of a TV screen. The PF-P300
(i.e., pattern flash-elicited P300) potentials were elicited by
two different kinds of checkerboard stimuli (A: 16 x 16
caskets, 50' of visual angle; B: 64 x 64 caskets, 12.5' of
visual angle) that were randomly flashed out of the gray
background of the TV monitor (A:B = 80:20; sensitivity,
100 |xV; number of averages, 250; bandpass, 1-30 Hz). To
obtain both the early stimulus-dependent and late event-
related components in one single potential, a bipolar deriva-
tion from Oz to Fz with Cz as reference electrode was chosen
(Taghavy and Kugler, 1988a).
In paradigm I (PI), the subjects were asked just to look at
the sequence of the checkerboard stimuli (passive condition
7
A
VA
N2
J5ms
Figure 1. P300 potentials (paradigm II) of three female subjects of age
group I (F.H., 25 yrs of age, top), age group III (P.U., 62 yrs of age,
middle), and age group IV (S.R., 98 yrs of age, bottom). As one can clearly
see, the N250 (N2) and P300 (P3) latencies are markedly prolonged in
advanced age, whereas the P300 amplitudes are only slightly reduced. The
test-retest-reliablity between both P300 potentials of each subject is high.
 P300 DYNAMICS IN COGNITIVE BRAIN AGING
ing the P300 peak. The P300 amplitude was determined as
the voltage difference between the N250 and P300 peaks,
respectively. The latencies of the N250 and P300 compo-
nents and the P300 amplitudes were manually measured by
one experienced investigator with the help of electronic
cursors. As previously shown (Taghavy and Kiigler, 1988a;
Taghavy et al., 1988; Kugler et al., 1994), the N250 and
P300 latencies are closely linked to stimulus discrimination
and processing time, whereas the P300 amplitudes are sensi-
tively reflecting different levels of visual attention and task
relevance. To investigate the dynamics of these cognitive
functions, the N250 and P300 latency differences as well as
the differences and ratios of the P300 amplitudes between
both paradigms I and II were also calculated intraindivi-
dually.
Furthermore, primarily stimulus-dependent components
(N75; P100) of visual potentials were evoked binocularly by
checkerboard reversal (PVEPs) (16 x 16 caskets, 50' of
visual angle; sensitivity, 100 |xV; bandpass, 1-30 Hz; num-
ber of averages, 120; time of analysis, 450 msec; stimulus
frequency, 1.9 Hz), to take into account possible alterations
of the P300 potentials by age-related changes in sensory
functions.
Statistics. — Since the variabilities of the P300 parame-
ters generally increased in the older age groups, we per-
formed the nonparametric Kruskal-Wallis test (two-sided)
for the overall analysis of differences between the four age
groups. For multiple comparisons of mean differences be-
tween pairs of age groups, we chose the Games-Howell test
that seems to be very robust, with groups having unequal «s
and heterogenous variances. Moreover, Wilcoxon's signed-
rank test was performed to evaluate paradigm effects intrain-
dividually. For the analysis of the aging-P300 interaction,
linear and polynomial regression analyses were calculated,
and multiple regression analyses were performed to test for
potential confounding effects on P300 parameters of visual
sensory functions (F-test, two-sided). Since both the corre-
lation coefficients and the levels of significance are not
appropriate tools to determine the best-fit regression model
for the aging-P300 interaction, an information criterion
(AIC) according to Akaike (1976) was calculated. This AIC
can be applied to estimate the goodness of fit yielded by a
model for a given data set according to the formula:
AIC = - 2 x logn (maximum likelihood)
+ 2 x (number of parameters)
= n x logn (sum squares residual)
+ 2 X (number of parameters).
The lower the AIC, the better the fit of the data provided by
the model. Furthermore, potential sex differences in the
quality of fit were assessed by the model selection criterion
(MSC; Micromath, 1992) that gives a normalized value and
can therefore be applied to samples of different sizes:
MSC = logn (sum square regression : sum square residual)
- 2 x P n.
where
P is the number of parameters and
n is the number of observations;
B5
the more the MSC approximates zero, the better is the fit
provided by the model. Finally, scatterplots of the residuals
of y against the fitted values of y were performed to visually
assess the fit of the aging-P300 interaction by a given
regression model. More details are given in the Results
section and the corresponding tables, as applicable.
RESULTS
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Exogenous pattern reversal visual-evoked potentials
(PVEPs). — In contrast to the P100 latencies that did not
change significantly (p = .2135) with age, the N75 latencies
and the PI00 amplitudes revealed significant age-related
decreases (Kruskal-Wallis, two-sided; p = .0496 and
.0008; see Table 1). The slopes of the linear regression lines
between age and both the N75 latencies and PI00 amplitudes
were-.09 msec/yr and-.06 (xV/yr, respectively (F-test;p =
.009 and .007, respectively). Multiple regression analysis
indicated that neither visual acuity nor the N75, PI00 laten-
cies or the PI00 amplitudes revealed significant correlations
with any of the P300 parameters {p > .05).
Endogenous visual event-related P300 potentials (PF-
P300). — As compared with paradigm I, the N250 latencies
were significantly shorter (p = .0001) in paradigm II,
whereas the P300 latencies were not different {p = .6994;
Wilcoxon signed-rank test, two-sided). The P300 ampli-
tudes in paradigm II were, in general, about 2.5 to 3.0 times
higher than in paradigm I (p = .0001). These results were
found for both the whole age group and the different sub-
groups, and reflect the dynamics of cognitive functions
between both conditions (Tables 2 and 3).
As compared with AG I, the N250 and P300 latencies of
both P300 paradigms I and II were markedly prolonged in
the older age groups (Kruskal-Wallis test, two-sided, p <
.02) (Table 2; Figures 1,2). Apart from the P300 latency of
PI in AG IV, the variability of the N250 and P300 latencies
increased in AG III and IV for both paradigms (Table 2;
Figure 2). The N250 and P300 latency differences between
Table 1. Pattern Reversal Visual-Evoked Potentials
in the Different Age Groups (I-IV)
I 11 III IV
(18-37) (38-57) (58-77) (78-98) p-value a = .05
N75 latency (ms)
82.3 81.9 79.4 77.5 .0496
±6.0 ±7.2 ±9.7 ±13.1
P100 latency (ms)
113.7 111.7 111.7 115.3 .2135
±7.1 ±6.8 ±9.7 ±15.6
PI00 amplitude (M-V)
8.8 7.6 6.7 4.6 .0008 I—III, I-IV, II-IV
±3.5 ±3.9 ±3.6 ±1.9
Notes: Values are means ± 1 SD; p, level of significance in the Kruskal-
Wallis test (two-sided); a = .05 for multiple comparisons between pairs of
age groups by means of the Games-Howell test. In contrast to the N75 and
P100 latencies, the P100 amplitudes showed significant (p < .05) differ-
ences between AG I—III, I-IV, and II-IV, respectively.
B6 KUGLER ET AL.

Table 2. Visual Event-Related P300 Potentials N250 latencies (Paradigm II)

in the Four Age Groups (AG I—IV)
340
AGI AGII AGIII AGIV
(18-37) (38-57) (58-77) (78-98) /7-value a = .05 320-
N250 latency (ms)
300-
PI 286.8 286.9 313.6 333.9 .0015 I—II1;I—IV;
280
±24.9 ±21.4 ±33.9 ±28.9 11—II1;1I—IV
I—II;I—III;I—IV; 260 (
PII 259.3 270.5 278.6 325.2 .0001

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±19.2 ±16.6 ±19.3 ±29.8 II—III;II—IV;III—IV 240'

P300 latency (ms)

AC I AC II AC 111 AC IV
PI 328.7 331.8 352.2 378.6 .0149 I-1V;II-IV
±30.8 ±25.9 ±45.1 ±26.8
Pll 320.9 333.9 343.8 406.6 .0001 I—1I;1—1II;I—IV;
±20.0 ±25.4 ±31.0 ±33.1 II-IV;III-IV . . P300 l a t e n c i e s (Paradigm II)
<mS)
400 • •
P300 amplitude (|xV)
440-
PI 6.1 6.3 5.1 3.1 .0274 I_1\/;II-1V 420
±3.4 ±2.7 ±2.9 ±1.2 400
/
Pll 13.0 13.1 10.1 7.9 .0003 I—Ill;l—IV; 380
±5.8 ±6.9 ±4.0 ±3.5 11—11I;II—IV
360
/
Notes: Values are means ± 1 SD. P300 parameters of paradigm I (PI, n 340 "
T -r
= 80) and paradigm II (Pll, n = 250) are given for each of the 4 age groups 320
(I—IV). p, level of significance in the Kruskal-Wallis test (two-sided); a =
.05, for multiple comparisons of pairs by means of the Games-Howell test. 300
The N250 and P300 latencies are prolonged in the older age groups,
whereas the P300 amplitudes are reduced. This was true for both para- AC1 AC II AGIII AG IV
digms. Interestingly, the variability of the latencies increases in the older
age groups, whereas that of the amplitudes decreases.

P300 amplitudes (Paradigm II)

20-

IS-

16-

14-
Table 3. P300 Dynamics Between Paradigm I and II
12-
in the Four Age Groups (AG I-IV)
10-
AGI AG II AG III AG IV
(18-37) (38-57) (58-77) (78-98) p-value
6-
N250 latency difference (Pll-Pl) (ms)
AC I AC II AC III AC IV
-22.5* -19.1* -30.6* -28.5* .4188
±20.0 ±17.3 ±29.9 ±35.5
P300 latency difference (Pll-Pl) (ms) Figure 2. Means and standard deviations of the N250, P300 latencies,
and P300 amplitudes (paradigm II). The N250 and P300 latencies are
-3.7 0.06 -7.6 14.1 .5675 prolonged with age and have higher variabilities. By contrast, the P300
±24.2 ±24.2 ±43.3 ±24.1 amplitudes are reduced in the older age groups and show smaller variabili-
ties. Similar results were also obtained for paradigm I.
P300 amplitude difference (Pll-Pl) (u,V)

7.33* 8.66* 5.84* 6.07* .5473

±5.3 ±5.8 ±4.0 ±3.3
P300 amplitude ratio (PillPI) PII and PI, however, did not reveal age-related changes
(Table 3).
2.7* 2.5* 2.7* 3.0* .6996
As compared with AG I and AG II, the P300 amplitudes
±1.5 ±1.1 ±1.4 ±0.8
of both paradigms were reduced (Kruskal-Wallis test, p =
Notes: Values are means ± 1 SD; n = 80. p, level of significance in the .0274 and .0003, respectively) in the older age groups.
Kruskal-Wallis test (two-sided). In contrast to the P300 latencies that did Furthermore, they showed a smaller variability in advanced
not show any paradigm effect, the N250 latencies were significantly shorter
and the P300 amplitudes significantly higher in Pll in all age groups. Age-
age (Table 2; Figure 2). Neither the ratios nor the differences
related differences in these P300 dynamics, however, were not found. of the P300 amplitudes between PII and PI, however, re-
*p = .0001 in Wilcoxon's signed-rank test for the intraindividual vealed significant reductions in the older age groups (Table
comparison of each P300 parameter between both paradigms. 3; Figure 3).
 P300 DYNAMICS IN COGNITIVE BRAIN AGING B7

Table 4. Linear and Piecewise Regression Analyses Between

Age (X) and Visual P300 (Y) of Paradigm I (PI) and II (PII)
Slope r r1 p-value
Linear regression (AG: 18-98)
N250 lat.
PI .723 .455 .207 .0001
PII .752 .592 .350 .0001
P300 lat.

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PI .722 .384 .148 .0005
PII .959 .574 .329 .0001
P300 ampl.
PI -.027 .165 .027 .1462
PII -.073 .246 .061 .0001
Piecewise linear regression (a. 18-57 yrs; b. 58-98 yrs)
N250 lat.
PI a .042 .02 .00038 .8831
b 1.059 .342 .117 .119
Plla .487 .307 .094 .0001
b 1.821 .685 .469 .0001
P300 lat.
PI a .101 .038 .001 .779
b 1.581 .400 .160 .065
Plla .603 .308 .095 .0001
b 2.441 .655 .429 .0001
P300ampl.
PI a .027 .096 .009 .4796
b -.02 .078 .006 .7288
Plla -.013 .024 .001 .7521
b -.057 .154 .024 .1705
Notes: Given are the slopes of the linear and piecewise regression lines,
the correlation coefficients (r), the square of r, denoting the percentage of
Figure 3. P300 potentials of both paradigm I (transient attention, dotted the variability of Y explained by X, and the level of significance (p) in the F-
line) and paradigm II (selective attention, solid line) are given for 3 subjects tests for both the P300 parameters of paradigm I (passive condition) and PII
of 3 age groups (F.H., 25 yrs of age, AG I, top; P.U., 62 yrs of age, AG II, (active condition).
middle; V.M., 80 yrs, AG IV, bottom). The P300 amplitude differences
between PI and PII of the older subjects remain unchanged as compared
with those of the younger subject.

In contrast to the N250 and P300 latencies that did not

Linear regression analyses revealed significant prolonga-
tions of the N250 and P300 latencies over age for both
paradigms (Table 4; Figure 4A and 4B). Interestingly, the
P300 latencies revealed a significantly greater slope in PII
(.959 msec/yr) than in PI (.722 msec/yr, p < .002). Further-
more, the P300 amplitudes showed only slight reductions
with increasing age in paradigm II that failed statistical sig-
nificance in paradigm I (Table 4). Piecewise linear regres-
sion analysis (Table 4) showed a 4- to 25-fold increase in the
N250 and P300 latency prolongation and P300 amplitude
reduction in subjects over age 58.
Searching for an optimal regression model, we applied an
information criterion (AIC, Akaike, 1976) to simple,
second-, and third-order polynomial regression models be-
tween age and the P300 parameters of both paradigms
(Figure 4, A-C). In descending order, third- and second-
order polynomial regression functions provided a much
better fit than linear models for both the N250, P300 laten-
cies, and P300 amplitudes of PI and PII, as shown by the
corresponding AIC values (Table 5).
show sex differences, the P300 amplitudes in PII were
slightly, yet significantly higher in the females (Table 6). A
more detailed regression analysis stratified for gender inter-
estingly showed that females had significantly higher slopes
(+1.148 msec/yr; linear regression) for the P300 latencies
than males ( + .789 msec/yr; t = -4.891, p < .0001).
Furthermore, the correlation coefficients of the regression
functions for the aging-P300 interactions were also signifi-
cantly higher for female subjects, as indicated by the model
selection criterion (Table 7). Interestingly, third-order poly-
nomial regressions were more appropriately fitting the
aging-P300 interactions than linear regression models in
both males and females (Table 7). According to these regres-
sions, the acceleration of the P300 latency increase seems to
start at the fifth decade in women, whereas it does not take
place before the sixth decade in men (Figure 5).
DISCUSSION
This study shows only slight changes in event-related
P300 potentials over a wide range of the adult life span,
suggesting a rather mild slowing of stimulus discrimination
B8 KUGLERETAL.

(m j y = .723x + 261.859, r2 = .207 y = .752x + 236.515, r2 = .35

(ms) 4QQ . . . . . . . .

380
380-
360

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360- • • • 340
340- 320
300
320- N2L (PI) N2L (PII)
280
300- 260
240' • • • • • • • •
280'
X 220 • • • •
. . . * * ' * "
260-
200'

20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE AGE

(ms) y = 300.147 - .976x + .016x2 y = 272.796 - .929x + .016x2

400 <ms) 400
380
380
360
360' 340
340 320
300'
320 N2L (PI) N 2 L (PII)
280'
300 260'
280' 240
220
260
200
240 180
20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE AGE

(ms) y = 398.742 - 7.439x + .142x2 - .001x3 y = 226.049 + 2.277x - .047x2 + 3.807E-4x3

400 (ms) 400

380' 380
360
360-
340
340 320
320 300
N2L (PI)
280-1 N2L(PII)
300 260
280-1 240
220
260
200
240 180
20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE AGE

Figure 4. Comparison of three different regression models for the aging-P300 interactions of both P300 paradigms. A, N250 latencies; B, P300 latencies;
C, P300 amplitudes. Given are linear, second- and third-order polynomial regression functions (from top to bottom) for the N250 (A), the P300 latencies (B),
and the P300 amplitudes (C) of both paradigm 1 (left) and PII (right). Overlap in the values of the scatter plots is handled by the method of fine cellulacion
showing the number of the same values at a given point by the number of leaflets in sunflower symbols. Aging is obviously associated with an accelerating
prolongation of the N250 and P300 latencies and a decelerating, yet relatively slight, reduction of the P300 amplitudes. These aging-P300 interactions are best
described by third-order polynomial regression functions, as indicated by the corresponding AIC values (see also Table 5). This could also be confirmed by
residual plots (Y, residuals of y; X, fitted values of y), which clearly demonstrated that nonlinear trends in the residuals vanished only after third-order
polynomial regression.

(Figure 4 continues next page)

 P300 DYNAMICS IN COGNITIVE BRAIN AGING B9

B
y = .722x + 304.23, r2 = .148 y = .959x + 291.269, r2 = .329

440 460-

420 440- ."

420- . . .
400
400-
380
380-
360 P3L (PI) . . . " ..IA !A!*V^---^*** P3L (Pll)
360-
340

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340-
320 •*• • • • •>•<—-r^ A • • • • • • •
320-
300 ^^JHKfT- tA. . • AA • A •
* * ' ! . . ". ' * 300- • • • • • • 4
280 . . .
280' t. " .
260 260"
20 30 40 50 60 70 SO 90 100 10 20 30 40 50 60 70 80 90 100
AGE AGE

y = 351.427 - 1.361x + .02x2 y = 340.462 - 1.321x + .022x2

440
420
400
380
360 P3L (PI) P3L (Pll)
340
i " " ."._i—-r*^r
320- • • . .
300
280 •

20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE

y = 430.197 - 6.511X + .12x2 - .001x3 y = 295.017 + 1.797x - .04x2 + 3.703E-4x3

(ms)

440-
420-
400- * .
380-
360- %
P3L (PI) P3L (PII)
' " * " ^ ^ \
340-
320
300 : ; • . . . . . • •
280 •

20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE

(Figure 4 continues next page)

(N250 latency) and evaluation time (P300 latency), as well tion). This indicates a higher increase in stimulus evaluation
as a minor decrease in visual attention capabilities (P300 time over age under active conditions such as selective
amplitudes). The age-related P300 alterations, however, attention and task relevance. These age-related prolonga-
accelerate from about 60 years of age onward, to peak in the tions of the P300 latencies are generally smaller than in
old and oldest old. Since neither visual acuity nor the early, previous visual (P3b: Strayer et al., 1987: + 1 . 1 1 msec/yr;
stimulus-dependent components of the PVEPs (N75, P100) Pfefferbaum et al., 1984: + 1 . 3 2 msec/yr; Picton et al.,
showed any correlation with the late P300 potential compo- 1984: + 1 . 4 1 msec/yr; P3a: Pfefferbaum et al., 1984:
nents, these P300 changes did obviously not result from age- + 1.54 msec/yr), auditory (P3b: Goodin et al., 1978a: 1.8
related declines in visual sensory functions. The amount of msec/yr; Yamashita et al., 1991: + 1 . 7 msec/yr; Knight,
the average age-related P300 latency prolongation is signifi- 1987: + 1 . 2 9 msec/yr; P3a: Polich et al., 1985: + 1 . 1 4
cantly higher in paradigm II ( + .959 msec per year) than in msec/yr; novel P3: Knight, 1987: + 1 . 1 3 msec/yr), and
paradigm I ( + .722 msec per year, linear regression func- somatosensory P300 studies (P3b: Yamaguchi and Knight,
BIO KUGLER ET AL.

y = -.027x + 7.008, r2 = ,027 y = -.073x + 15.396, r2 = .061

40

P3A (Pin
P3A (PI)

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! !

20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100
AGE

(pV) y = 4.134 + .lx - .001x2 y = 12.635 + .055x - .001x2

•
14

12-
10
8 P3A (PI) P3A ( P i n

4'

2 : . . * . ^ ^

20 30 40 50 60 70 80 90 100 20 30 40 50 60 70 80 90 100
AGE

(MV) y = -1.93 + .496x - .009x2 + 4.564E-5x3 y = Z108 + .777x - .016x2 + 8.572E-5x3

40

P3A (PI) P3A (PII)

• •

20 30 40 50 60 70 90 100 10 20 30 40 50 60 70 80 90 100
AGE

1991: +1.28 msec/yr; novel P3: Yamaguchi and Knight,
1991: +1.72 msec/yr). This may not only be due to differ-
ences in stimulus modality (Pfefferbaum et al., 1984; Picton
et al., 1984; Barrett et al., 1987) or other stimulus features,
but rather may depend on different degrees of task difficulty
(Knight, 1987), on differences in P300 measurement tech-
niques (Fein and Turetsky, 1989), and, finally, on differ-
ences in the age distribution and the health status of the study
populations.
In contrast to the large body of data on the age-related
changes in P300 latency, there are only relatively few reports
on the latencies of the "preceding negativities" (N2 or
N250). In this study, the N250 latencies also revealed sig-
nificant prolongations over age (see also Figures 1-3 and
Table 2). These age-related N250 latency prolongations that
ranged between .73 and .75 msec/yr for P300 paradigm I and
II, respectively, are in good line with those of other studies
(Picton et al., 1984: +.64 msec/yr; Coyle et al., 1991:
+ .90 msec/yr). The amount of these latency prolongations
is much greater than that of the early exogenous components
such as the N75 (-.09 msec/yr) or P100 of the PVEPs (-.036
msec/yr, linear regression), but smaller than that of the P300
latencies of PII ( + .959 msec/yr). This also supports the
notion of an exceptional role of the N250 between the
exogenous primary and endogenous P300 complex
(Taghavy and Kiigler, 1988a).
 P300 DYNAMICS IN COGNITIVE BRAIN AGING Bll

Table 5. Different Kinds of Regression Models for the Best Fit Table 6. Sex Differences Between the P300 Parameters
of the Aging-P300 Interaction of Both P300 Paradigms

N2501at. P3001at. P300ampl. Males Females p-value

P300 parameters of paradigm I (n = 80) N250 lat. (ms)
Linear regression PI 295.3 293.2 .697
Intercept 261.9 304.2 7.0 ±29.3 ±28.9
Slope .723 .722 -.027 PII 269.8 272.9 .790
.455 .384 .165 ±24.0 ±25.7

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.207 .148 .027
P300 lat. (ms)
F-test p-value .0001 .0005 .1462
AIC 877.4 897.4 521.58 PI 340.9 332.8 .482
Second-order polynomial regression ±37.5 ±30.7
351.4 PII 335.1 333.4 .319
Intercept 300.2 4.13
x -.976 -1.361 .10 ±30.1 ±33.3
x2 .016 .020 -.001 P300 ampl. (p-V)
r .501 .441 .224
PI 6.0 5.57 .923
rJ .251 .194 .05
.0003 .1409 ±3.6 ±2.6
F-test p-value .0001
PII 11.2 13.3 .004
AIC 872.9 892.9 519.7
±5.6 ±6.2
Third-order polynomial regression
P300 ampl. ratio
Intercept 398.7 430.2 -1.93
x -7.439 -6.511 .496 2.62 2.68 .842
x2 .142 .12 -.009 ±1.41 ±1.22
-.001 -.001 .000046
.538 .461 .253 Notes: Values are means ± SD of the P300 parameters for male and
r2 .212 .064 female subjects in both the passive (PI) and active (PII) P300 paradigms, p,
.289
level of significance in the Mann-Whitney t/-test for unpaired samples. The
F-test p-value .0001 .0004 .1711 P300 amplitudes were higher in females than in males.
AIC 868.6 891.2 518.5
P300 parameters of paradigm II (n = 250)
Linear regression
Intercept 236.5 291.3 15.40
Besides the P300 latencies of PI, the variabilities of the
Slope .752 .959 -.073 N250 and P300 latencies increased in age groups III and IV.
.592 .574 .246 As compared with the increase in P300 latency variability
.350 .329 .061 that is in line with other studies (Hegerl et al., 1985; Gordon
F-test p-value .0001 .0001 .0001 et al., 1986; Kraiuhin et al., 1986), our results on the
AIC 2885.6 3016.0 2251.1 age-related variability of the N250 latency are more contro-
Second-order polynomial regression versial: Although Patterson et al. (1988) as well as Taghavy
Intercept 272.8 340.5 12.64 and Kugler (1988a) did not report an increased variability of
x -.929 -1.321 .055 the N250 latency in their elderly subjects (age range: 57-81
x2 .016 .022 -.001 and 18-60 years, respectively), we found an age-related
r .652 .641 .262 increase in the variabilities of the N250 latency in this larger
r* .426 .411 .069 sample of subjects (age range: 18-98 yrs). It was more
F-test p-value .0001 .0001 .0002
pronounced under active (PII, +50%) than passive condi-
AIC 2854.7 2983.9 2249.0
tions (PI, + 20%), and was primarily found in subjects over
Third-order polynomial regression age 60. Therefore, these discrepancies may be mainly
Intercept 226.1 295.0 2.11 caused by differences in both the age distribution of the
x 2.277 1.797 .777 study population and the experimental design. Besides in-
x2 -.047 -.04 -.016 creased variabilities, the N250 and P300 latency differences
x3 .00038 .00037 .000086
between paradigm II and I did not significantly change with
r .664 .647 .288
age, suggesting that the dynamics in stimulus discrimination
r2 .441 .419 .083
F-test p-value .0001 .0001 .0001
and evaluation time remain basically intact even in old age.
AIC 2847.7 2980.3 2245.0 The P300 amplitudes were significantly reduced in PII
(selective attention) and in PI (transient attention), whereas
Notes: AIC, an information criterion for the comparison of the goodness the P300 amplitude ratios between PII and PI (dynamics of
of fit between X (age) and Y (P300 parameters) provided by different
regression models; the smaller the AIC value, the better the fit yielded by visual attention) remained unchanged. The age-related de-
the model (see Methods). The best-fit regression models for the aging-P300 crease in the P300 amplitudes is rather small in both para-
interactions are third-order polynomials. digms (PII: -.07 |xV/yr; PI: -.02 jiV/yr), while other authors
reported a P300 amplitude reduction ranging from - . 14 jxW
yr up to -.25 (xV/yr over the whole life span (Goodin et al.,
1978a; Picton et al., 1984; Hegerl et al., 1985; Yamaguchi
B12 KUGLER ET AL.

Table 7. Sex Differences in the Regression Functions (ms) ym = 263.462 + 3.872x - .077x2 + .001x3
Between the P300 Parameters and Age 475

450
N250 lat. P300 lat. P300 ampl.
m/f m/f m/f 425

400
Linear regression
375 males
Slope .69/.82 .79/1.15 -.O8/-.O7
350
r .547.65 .49/.66 .27/.23
r2 .29/.42 .247.44 .07/.05 325

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F-test p-value .0001 .0001 .0009/.02I 300
AIC 1615.8/1100.2 1696.5/1150.3 1228.5/848.1 275
MSC -.90/-. 35 -1.19/—.28 -2.57/-2.96
10 20 30 40 50 60 70 80 90 100
Second-order polynomial regression AGE

Intercept 258.1/285.1 327.3/347.5 11.1/12.1

X —.31/—1.37 -.59/-1.73 .10/. 12
x2 .01/.02 .01/.03 -.002/-.002 (ms) yf = 326.288 -.262x- .002x2 + 1.717E-4x3
r .567.75 .51/.75 .29/. 26 475-
r2 J2/.56 .26/.57 .09/.07 450- •
F-test p- value .0001 .0001 .002/.027
AIC 1611.4/1072.2 1691.7/1124.4 1226.5/846.1
425' .V.
MSC -.80/.21 -1.06/. 23 -2.40/-2.64 400'

375' females.
Third-order polynomial regression
350- A
• "A"
Intercept 191.6/256.4 263.5/326.3 -1.24/7.47 *•
325
X -4.35/.61 3.87A-.26 .97/.44
300- • • ••
x2 -.09/-.02 -.08/-.002 -.02/-.008 •

x2 .001/.0002 .001/.0002 .00011/.00004 275- •

r .58/.75 .S3/.75 .327.27
r* .34/.57 .28/.57 .10/.07
F-test p-value .0001 .0001 .002/.057
AIC 1606.3/1070.6 1688.9/1123 1224.1/845.7
MSC -.70/-. 31 -.99/.24 -2.227-2.59
Notes: The relationship between age and the P300 parameters is best
approximated by kubic regression models for both males and females, as
indicated by the AIC criterion. In females, the aging-P300 interaction is
much closer than in males, as shown by both the correlation coefficients and
the MSC criterion. AIC, an information criterion for the comparison of the
goodness of fit between different regression models; the smaller the AIC
value, the better the fit provided by the model (see Methods). MSC, model
selection criterion; this provides a normalized figure for the goodness of fit
of a regression model and can therefore be applied for the male-female
comparisons. The more the MSC value approximates zero, the better the fit
provided by the model, m, males; f, females.
and Knight, 1991). These differences may be due to con-
founding variables such as stimulus modality (Pfeffer-
baum et al., 1984; Picton et al., 1984), the subjects' re-
sponse condition (Barrett et al., 1987), and the applied
measurement technique (Fein and Turetsky, 1989). Further-
more, it is well known that the P300 amplitude distribution
becomes more equipotential with advancing age, because
the P300 amplitudes remain constant or even slightly in-
crease frontally (Yamaguchi and Knight, 1991) while de-
creasing centroparietally (Goodin et al., 1978a). Therefore,
the peculiar kind of electrode location on the scalp for P300
potential derivations may be a strong independent factor
influencing the age-related P300 amplitude changes. Since
we have derived P300 potentials bipolarly from Oz to Fz
with Cz as reference electrode to obtain both the early
exogenous VEP components and the later endogenous P300
components in one single potential, those inverse age-
related P300 amplitude effects may have partially offset
10 20 30 40 50 60 70 80 90 100
ACE
Figure 5. Comparison of the third-order regression functions for the P300
latencies of males (m) and females (0- As the regression lines indicate, the
acceleration of the age-related P300 latency prolongations starts about a
decade earlier in females (at approximately the 5th decade) than in males (at
approximately the sixth decade).
themselves, resulting in this relatively small age-related
P300 amplitude decrease. And finally we found, in line with
the results of Mullis et al. (1985), the P300 amplitudes even
to slightly increase until about the fifth decade, which
consequently diminishes the P300 amplitude decrease over
the whole life span. Interestingly, the variability of the P300
amplitudes (PII), rather, decreased in advanced age.
Hegerl et al. (1985) and Kraiuhin et al. (1986) also reported
slight decreases in the P300 amplitude variability in older
age, especially at parietal locations. Although this phenome-
non remains largely unclear at present, it may be of only
minor importance, since the variabilities of the P300 ampli-
tudes in PI as well as those of the P300 amplitude ratios
between PII and PI remain constant, and the P300 ampli-
tudes, as compared with the P300 latencies, have only a very
limited diagnostic power.
In contrast to previous results in a smaller sample of
subjects (Taghavy and Kiigler, 1988b), we found the fe-
males to have significantly, yet only slightly higher P300
amplitudes in paradigm II in the whole age group, whereas
the N250 and P300 latencies did not show any significant sex
differences in either P300 paradigm. These findings are in
line with those of Picton et al. (1984) and Yamashita et al.
(1991), but in contrast to those of Mullis and co-workers
(1985), who did not find gender effects on the P300 ampli-
 P300 DYNAMICS IN COGNITIVE BRAIN AGING
tudes. Furthermore, the aging-P300 interactions did show
higher correlation coefficients in the different kinds of re-
gression models for the females. These interesting results
indicate that in women a higher percentage of P300 variabil-
ity can be explained solely by age, whereas in males addi-
tional factors may contribute. In contrast to Hegerl et al.
(1985), who reported an age-related P300 latency increase of
1.3 msec per year for men and of only .25 msec per year for
women in an auditory oddball paradigm, we actually found a
significantly greater P300 latency increase in the females
(+1.148 msec/yr vs .789 msec/yr in men, p < .0001).
Furthermore, third-order polynomial regression functions,
which provided the best fit for the aging-P300 interactions of
both males and females, indicated that the acceleration of the
P300 latency increase may start about a decade earlier in
females than in males. Whether this greater and perhaps
earlier P300 latency prolongation in females may be an
electrophysiological sign for the earlier development of age-
related brain atrophy reported in anatomical (Hubbard and
Anderson, 1983) as well as radiological investigations (Ha-
tazawa et al., 1982), clearly awaits confirmation by direct
cross-correlational investigations. Interestingly, these sex
differences in age-related changes of cognitive processes
could be associated with the estrogen-deficiency state in
postmenopausal women. First, recent experimental data
indicate that conjugated estrogen acts on cholinergic neurons
as a growth factor (Honjo et al., 1992). Second, since
estrogen and low-affinity nerve growth factor receptors are
co-localized in cholinergic neurons of the rodent and primate
basal forebrain, estrogen may act together and, perhaps
synergistically, to regulate neuronal survival, differentia-
tion, regeneration, and plasticity (Toran-Allerand et al.,
1992). Third, the risk for Alzheimer dementia that is more
prevalent in elderly women (Jorm et al., 1987) appears to
decrease in postmenopausal women who have taken estro-
gens for replacement therapy (Henderson et al., 1994).
Fourth, preliminary data suggest that female patients with
Alzheimer dementia receiving conjugated estrogen therapy
improve on dementia test scores (Honjo et al., 1989). Fi-
nally, these data seem to be in good accordance with the
putative role of cholinergic deficits in both age-related mem-
ory impairment and Alzheimer dementia. Because of the
potential preventive and therapeutic implications of these
results, at least for women, the clarification of this matter
would be of paramount importance.
In contrast to numerous reports that argue in favor of
linear or piecewise linear regression functions (Goodin et
al., 1978a; Syndulkoetal., 1982; Pictonetal., 1984;Polich
et al., 1985; Gordon et al., 1986; Coyle et al., 1991), our
present data indicate that third-order polynomial regression
functions provide the best fit for the relationship between
aging and visual P300 potentials. These aging-P300 interac-
tions were similar for both P300 paradigms and both sexes.
Our results are therefore more consistent with the findings of
both Brown etal. (1983) for the auditory and Mullis and co-
workers (1985) for the visual P300 oddball paradigm, who
favored second-order polynomial regression models. Be-
sides methodological differences, these controversial results
may primarily depend on differences in the age distribution
of the study groups: In contrast to previous results on a
B13
smaller sample of subjects (Kiigler et al., 1993b), these
third-order polynomial trends in the aging-P300 interactions
have emerged only after the inclusion of a larger number of
very old subjects into the analysis. The critical question,
however, is what the meaning of these nonlinear aging-P300
interactions may be. Although a clear-cut answer as to the
exact aging mechanisms resulting in a third-order polyno-
mial rather than a linear regression function seems elusive at
present, there are some lines of evidence that strongly argue
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in favor of nonlinearity as a basic principle not only of aging
in general, but also of brain aging in particular.
First, aging itself can be defined by the pattern of mortal-
ity experienced by adult human populations: The age-
specific mortality rate is very well approximated by a simple
exponential according to the formula fxx = |x0 e" (Gompertz,
1825).
Second, neuronal degeneration and replacement gliosis,
which may be regarded as the primary aging changes of the
brain, become most pronounced in the seventh, eighth, and
ninth decades of life (Adams and Victor, 1993), whereas
before a depletion of the neuronal population in the neocor-
tex could not be demonstrated (Haug et al., 1983). Presum-
ably, these processes may result in an age-related exponen-
tial decrease in brain weight and brain volume on the one
side (Davis and Wright, 1977; Debakan and Sadowsky,
1978), and an exponential increase in brain atrophy on the
other (Barren et al., 1976; Zatz et al., 1982; Stafford et al.,
1988; Kaye et al., 1992). Since there is no clear-cut relation-
ship between these accelerating morphological changes and
the functional level during normal aging (Kaye et al., 1992),
a protective excess of cells could be proposed that must be
lost before functional deficits appear. Furthermore, even the
aging brain can react to cell loss by the expansion of
dendritic trees of surviving neurons and the development of
new synapses (Buell and Coleman, 1979). This compensa-
tory mechanism may additionally attenuate the functional
consequences of age-related morphological changes and
delay them into old age.
Third, recent neurophysiologic data indicate that age-
related changes of beta-2 and beta-3 EEG waves were also
best described by third-order polynomial and exponential
regression functions (Duffy et al., 1992), whereas other
EEG components such as theta and delta waves revealed
linear trends over age. Although an exact relationship be-
tween the age-related changes of event-related P300 poten-
tials and those of the spontaneous EEG has not yet been
accomplished, some data suggest P300 potentials to be
associated with decreases in beta activity in simultaneous
EEG epochs (van Dijk et al., 1992). If the relationship
between P300 potentials and EEG-beta-activity could be
confirmed during aging, this would also buttress the non-
linearity of the aging-P300 interactions.
And finally, additional support comes from psychological
research on the aging mind. Influential concepts of intelli-
gence have employed a two-process categorization that jux-
taposes "cognitive mechanics" (fluid intelligence) with
"cognitive pragmatics" (crystallized intelligence) (Baltes et
al., 1984). Although the former is primarily determined by
the evolution-based neurophysiological architecture of the
mind and is, therefore, strongly dependent on genetic-
B14 KUGLER ET AL.
biological-health factors, the latter primarily reflects the
impact of human agency and cultural knowledge. Interest-
ingly, these two categories of intelligence display very
different life-span courses of change (Horn, 1970). While
the former displays an exponential decline, especially in the
elderly, the latter shows stability and even positive changes
in persons who reach old age without brain pathology. This
progressive decrease in "cognitive mechanics" appears to
be in good accordance with the age-related changes in P300
potentials that can be considered as electrophysiological
substrates of some elementary brain processes of sensory
information discrimination, processing, and categorization
(Fabiani et al, 1986). The progressive decline of P300
potentials with advancing age on the one side, and their high
sensitivity as to dementias on the other, support this assump-
tion. P300 potentials, however, also appear to be involved to
some degree in the planning and control of behavior in the
future (Donchin and Coles, 1988) and thus may be addition-
ally influenced by cultural factors. Therefore, one could
tentatively hypothesize that a weighed combination of both
biological-health related and culture-dependent factors with
a predominance of the former, may result in the nonlinear
regression between P300 and aging. In our view, nonlinear
regression functions appear to be more compatible with
aging-P300 interactions than linear regression models. They
may primarily reflect the plasticity of the human brain that
can compensate the neurobiological effects of aging over a
wide age span, and perhaps some positive effects of cultural
factors as well. In old age, reduced compensatory mecha-
nisms and an increased comorbidity primarily and/or sec-
ondarily affecting cognitive brain functions eventually result
in an accelerating cognitive decline.
Our findings may also have strong impact on the clinical
utility of the P300 event-related potentials. Since third-order
polynomials obviously reflect the age-related P300 changes
more accurately than linear regression functions, appropriate
models for the calculation of corresponding confidence in-
tervals have to be developed that also consider the age-
related increase in the variability of the P300 components.
At present, it appears reasonable to obtain P300 normal
values for each different age group, especially for subjects
over age 80. Furthermore, the diagnostic power of P300
potentials has to be delineated for each disorder of interest,
since it depends not solely on the age-related P300 changes
in and of themselves, but also on the degree of the disease-
related P300 alterations and the age distribution of the
subjects with the disease (Goodin et al., 1978b; Kraiuhin et
al., 1986;Kiigleretal., 1992).
In conclusion, event-related P300 potentials appear to be
promising electrophysiological tools for the analysis of cog-
nitive aspects of human brain aging. As indicated by the
squares of the correlation coefficients, the visual P300 po-
tentials elicited under conditions of selective attention and
task-relevance (PII) are more appropriate for this purpose
than those of PI. Furthermore, the N250 and P300 latencies
better reflect cognitive aging than do the P300 amplitudes.
Although the percentage of variability of the N250 and P300
latencies that is explained by aging alone is between 14 and
44%, and therefore relatively small, this does not disqualify
P300 potentials as biomarkers for cognitive human brain
aging. First, the P300 potentials reflect aging effects much
better than the earlier, stimulus-dependent PI00 components
of the PVEPs (r2: .005-.073). Second, given the complexity
of both the spectrum of human cognitive functions of which
P300 potentials cover only a part and human brain aging, it is
not surprising at all that a rather small percentage of the P300
variability can be explained by aging, but it is rather aston-
ishing that this figure is as high as it is. And finally, from
another viewpoint, the fact that the P300 variability is not
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totally explained by aging can even be considered as an
advantage, since P300 consequently can reflect other condi-
tions such as memory disorders as well.
ACKNOWLEDGMENTS
We are grateful to W. Braun, Institute for Research and Development,
University of Witten/Herdecke, for his excellent statistical advice and
critical review of the manuscript.
Address correspondence and requests for reprints to Dr. Christian F.A.
Kiigler, Chair of Internal Medicine and Gerontology, Institute of Gerontol-
ogy, University of Erlangen-Niirnberg, Ilnd Department of Internal Medi-
cine, Flurstr. 17, D-90340, Niirnberg, Germany.
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Received January 3, 1994
Accepted November 28, 1994