C-reactive protein is related to memory and medial temporal brain volume
in older adults
Brianne Magouirk Bettchera,⇑, Reva Wilheima, Taylor Rigbya, Ralph Greenb, Joshua W. Millerb,
Caroline A. Racinec, Kristine Yaffed, Bruce L. Millera, Joel H. Kramera
aDepartment of Neurology, University of California, San Francisco, Memory and Aging Center, San Francisco, CA, USA
bDepartment of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, USA
cDepartment of Neurological Surgery and Radiation Oncology, University of California, San Francisco, CA, USA
dDepartment of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
a r t i c l e i n f o
Received 6 June 2011
Received in revised form 29 July 2011
Accepted 30 July 2011
Available online 6 August 2011
a b s t r a c t
Recent research suggests a central role for inflammatory mechanisms in cognitive decline that may occur
prior to evidence of neurodegeneration. Limited information exists, however, regarding the relationship
between low-grade inflammation and cognitive function in healthy older adults. This study examined the
relation between inflammation, verbal memory consolidation, and medial temporal lobe volumes in a
cohort of older community-dwelling subjects. Subjects included 141 functionally intact, community-
dwelling older adults with detectable (n = 76) and undetectable (n = 65) levels of C-reactive protein. A
verbal episodic memory measure was administered to all subjects, and measures of delayed recall and
recognition memory were assessed. A semiautomated parcellation program was used to analyze struc-
tural MRI scans. On the episodic memory task, analysis of covariance revealed a significant CRP group
by memory recall interaction, such that participants with detectable levels of CRP evidenced worse per-
formance after a delay compared to those with undetectable levels of CRP. Individuals with detectable
CRP also demonstrated lower performance on a measure of recognition memory. Imaging data demon-
strated smaller left medial temporal lobe volumes in the detectable CRP group as compared with the
undetectable CRP group. These findings underscore a potential role for inflammation in cognitive aging
as a modifiable risk factor.
? 2011 Elsevier Inc. All rights reserved.
The systemic restructuring of the immune system may contrib-
ute to many age-associated disorders, including cognitive dysfunc-
tion and neurodegeneration (Glass et al., 2010; Ownby, 2010).
Although inflammatory processes represent a normal response to
pathogen invasion that are critical to maintaining homeostasis,
sustained neuroinflammation has deleterious effects on neurolog-
ical functioning that can disrupt cognition and influence brain
structure. Recent research on inflammation and Alzheimer’s
disease suggests a central role for inflammatory mechanisms in
cognitive decline (Akiyama, 1994; Schmidt et al., 2002; Weaver
et al., 2002; Holmes et al., 2003; Yaffe et al., 2004; Dik et al.,
2005; Dimopoulos et al., 2006; Alley et al., 2008; Bermejo et al.,
2008; Locascio et al., 2008; Forlenza et al., 2009) that may predate
evidence of neurodegeneration (Schuitemaker et al., 2009);
however, a paucity of information exists regarding the relationship
between low-grade inflammation, cognitive functioning, and brain
structure in healthy older adults (Ravaglia et al., 2005; Wersching
et al., 2010; Simen et al., 2011).
More specifically, inflammation has been implicated in memory
performance in older adults (Gunstad et al., 2006; Noble et al.,
2010) and in animal models (Semmler et al., 2005; Hein et al.,
2010). Chronic inflammation impairs hippocampal functioning by
disrupting long-term potentiation and memory formation (Murray
and Lynch, 1998; Semmler et al., 2005; Lin et al., 2009; Terrando
et al., 2010), suggesting that protracted inflammatory processes
may serve as a contributing factor to episodic memory dysfunction.
Additionally, recent studies indicate that non-demented, older
adults with higher levels of systemic inflammatory markers per-
form worse on verbal memory tests at baseline (Teunissen et al.,
2003; Noble et al., 2010) and are at risk for future decline (Yaffe
et al., 2004; Komulainen et al., 2007); however, the relationship be-
tween inflammation and memory is not consistent, as additional
cross-sectional (Wersching et al., 2010) and longitudinal studies
(Hoth et al., 2008) have failed to find an appreciable connection
between inflammation and memory function. The variability in
0889-1591/$ - see front matter ? 2011 Elsevier Inc. All rights reserved.
⇑Corresponding author. Address: Department of Neurology, University of
California, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143-1207, USA.
Fax: +1 415 476 5573.
E-mail address: email@example.com (B.M. Bettcher).
Brain, Behavior, and Immunity 26 (2012) 103–108
Contents lists available at ScienceDirect
Brain, Behavior, and Immunity
journal homepage: www.elsevier.com/locate/ybrbi
findings may stem from methodological reliance on composite
scores, which may mask important nuances in encoding and
consolidation processes, particularly in healthy older adult popula-
tions who do not evidence gross memory impairments. Further-
more, the relative lack of neuroimaging data renders it difficult
to interpret prior evaluations of the relationship (or lack thereof)
between verbal memory and laboratory indices of inflammation
(Noble et al., 2010), as discrepancies in results may be due to
changes in cognitive function that are not dependent on the medial
temporal lobes. Clearly, the association between inflammation and
cognitive functioning remains relatively understudied, and little is
known about the mechanisms by which inflammation and age
interact to affect memory functioning.
between inflammation, verbal memory, and medial temporal lobe
volumes in a cohort of older adults. We hypothesized that individu-
als with detectable blood levels of C-reactive protein (CRP) would
have poorer memory consolidation and smaller left medial-tempo-
ral lobes (MTL) than those with undetectable levels of CRP. We se-
lected the left medial temporal lobe as an anatomic region of
interest, as this area is known to mediate verbal memory consolida-
tion (Schacter and Wagner, 1999; Squire et al., 2004). Considering
the animal literature linking inflammation to perturbation in mem-
ory consolidation (Semmler et al., 2005; Terrando et al., 2010), we
hypothesized that individuals with detectable levels of CRP would
demonstrate worse performance on delayed free recall, even after
accounting for their overall verbal learning. We also chose to evalu-
the ability to encode and consolidate verbal information, specifi-
cally recognition memory (Libon et al., 1998; Price et al., 2009).
A sample of 141 neurologically healthy older adult participants
was selected from the University of California, San Francisco Mem-
ory and Aging Center database based on the availability of labora-
tory blood work assessment (i.e., fasted blood draw); in addition, a
subset of 133 individuals received a 3T structural MR scan. All 3
testing sessions occurred within a 90 day period. Participants were
recruited from a larger umbrella study on healthy aging and cogni-
tion (i.e., Myelin and Aging study, Larry J. Hillblom foundation),
and were between the ages 65 and 90 years. Participants were re-
viewed in a screening visit, which entailed an informant interview,
neurological examination, and cognitive testing. Inclusion as a
‘‘neurologically healthy’’ participant was based on several criteria,
including a Mini-Mental State Exam score of >25, Clinical Demen-
tia Rating score of 0, and no subject or informant report of signifi-
cant cognitive decline during the previous year. Participants were
excluded if they had a major psychiatric disorder, neurological
conditions affecting cognition (e.g., Parkinson’s disease, epilepsy;
large vessel infarct), dementia or mild cognitive impairment, sub-
stance abuse, significant systemic medical illnesses (e.g., cancer;
renal failure), current medications likely to affect CNS functions
(e.g., long-active benzodiazepines), significant sensory or motor
deficits that would interfere with cognitive testing, current depres-
sion (Geriatric Depression Scale Score greater than 15 of 30)
(Yesavage et al., 1982), or insulin-dependent diabetes. All available
information regarding medical history and medication use was
garnered via participant self-report. Demographic, health/lifestyle,
and cognitive variables are reported in Table 1. The study was
approved by the UCSF committee on human research, and all
subjects provided written, IRB-approved informed consent before
2.2. Memory assessment
Participants were administered the California Verbal Learning
Test, 2nd edition (CVLT-II), a widely used and well normed mea-
sure of episodic memory (Delis et al., 2000). Subjects were read a
list of 16 words (List A) presented over five learning trials, and in-
structed to recall as many words as they could for each trial. They
were then presented with an interference list (List B) composed of
16 new words. In order to assess a widely used index of episodic
memory on the CVLT-II, we focused our primary analysis on the
delayed recollection of List A words (i.e., Short Delay Free Recall),
as this provides a relative pure measure of consolidation without
categorical cueing. Considering that we were also interested in
supplemental measures that have been associated with medial
temporal lobe functioning, we included the recognition memory
trial as a secondary dependent variable.
The recognition memory trial consists of the 16 target items and
32 distracters presented in a randomly ordered array; subjects
were to respond ‘‘yes’’ if the item was from the target list and
‘‘no’’ if it was not. Level of performance on a yes–no recognition
memory test is reflected in the number of correct hits and false-po-
sitive errors. These data yield a measure of recognition memory
that has been adapted from signal detection theory: recognition
discriminability. Discriminability refers to the ability to distinguish
target words from distracter words, and it is widely considered to
be the best measure of recognition memory accuracy. The recogni-
tion discriminability index, or d0, is analogous to a contrast z score
reflecting the absolute difference in standard deviation units be-
tween the subjects hit rate and false-positive rate.
2.3. Laboratory biomarker of inflammation data and analysis
Blood was collected into serum separator tubes and left to clot
at room temperature for 30–60 min. The blood was then centri-
fuged at 2500 rpm (1300–1800 ? g) at room temperature for
15 min. Serum was stored at ?80 ?C until analysis. C-reactive pro-
tein (CRP), an acute-phase protein and marker of system low-grade
Demographics and unadjusted verbal memory performance by C-reactive protein
(n = 65)
(n = 76)
Female sex (%)
History of hypertension (%)
Current smoker (%)a
Ever smoker (%)
Body mass indexb
Non-aspirin NSAID use (%)
Aspirin use (%)
Statin use (%)
Geriatric depression scale
CVLT-trial 5 correct
CVLT-short delay recallc
All values represent mean (standard deviation). Dichotomous variables represent
CVLT = California verbal learning test-II.
D0= Recognition discriminability.
aSignificant group difference (p < 0.05).
bSignificant group difference (p < 0.01).
cSignificant group by trial (learning vs. short delay recall) interaction after
controlling for covariates, p = 0.01.
dSignificant group difference after controlling for covariates, p = 0.05.
B.M. Bettcher et al./Brain, Behavior, and Immunity 26 (2012) 103–108
inflammation, was measured by immunoturbidimetric assay (Uni-
versity of California, Davis Medical Center Clinical Laboratory, Da-
vis, CA). This was not a high-sensitivity assay; thus, the lower
detection limit was 0.1 mg/dL. Considering that a large number
of our healthy adults did not evidence detectable levels of inflam-
matory markers, we divided the participants into two groups:
detectable CRP and undetectable CRP (Kravitz et al., 2009). Of our
141 participants, 65 individuals were classified in the undetectable
CRP group, and 76 were in the detectable CRP group (mean = 0.34;
range = 0.1–2.4 mg/dL). Notably, elevations in CRP were under
3.0 mg/dL, which has been used as a benchmark for acute inflam-
mation (as noted in Fig. 1 of Wersching et al., 2010). Although par-
ticipants were not extensively screened for acute inflammation,
the range of CRP values suggests that acute inflammation or illness
is unlikely. Furthermore, no significant between-group differences
were noted in demographic variables, depression scores, or MMSE
(p > 0.05 for all), as shown in Table 1.
2.4. Neuroimaging data and analysis
MRI scans were obtained on a 3.0 Tesla Siemens (Siemens, Iselin,
the UCSF Neuroscience Imaging Center. Whole brain images were
acquired using volumetric magnetization prepared rapid gradient-
echo sequence (MPRAGE; TR/TE/TI = 2300/2.98/900 ms, a = 9?).
The field of view was 240 ? 256 mm, with 1 ? 1 mm in-plane reso-
lution and 1 mm slice thickness.
The T1 MPRAGE structural MR images were analyzed using
Freesurfer, which is documented and freely available for download
online at: http://surfer.nmr.mgh.harvard.edu. Previous publica-
tions have provided detailed descriptions and validation of the
software (Dale et al., 1999; Fischl et al., 2001; Segonne et al.,
2004). Freesurfer is a surface-based structural MRI analysis tool
that segments white matter and tessellates both gray and white
matter surfaces. The procedure, in brief, involves the removal of
non-brain tissue using a hybrid watershed/surface deformation
procedure (Segonne et al., 2004) and intensity normalization (Sled
et al., 1998), followed by automated Talairach transformation and
volumetric segmentation of cortical and subcortical gray and white
matter, subcortical limbic structures, basal ganglia and ventricles
(Fischl et al., 2002, 2004). Estimated total intracranial volume
(ICV) is calculated via an atlas normalization procedure. The sur-
facing algorithm uses intensity and continuity data, and corrects
topological defects to generate a continuous cortical ribbon used
to calculate gray matter volume and thickness (Fischl and Dale,
2000; Fischl et al., 2001; Segonne et al., 2007), a procedure vali-
dated against histological analysis (Rosas et al., 2002) and manual
measurements (Kuperberg et al., 2003). This cortical surface is then
inflated and registered to a spherical atlas and parcellated into
regions of interest (ROI) based on gyral and sulcal structure (Fischl
et al., 1999; Desikan et al., 2006). Region of interest was the left
medial temporal lobe (MTL), which was defined as the left hippo-
campus, parahippocampal gyrus, and entorhinal cortex. In order to
assess whether our results were primarily related to medial tem-
poral lobe volume, we also examined the left temporal neocortex
(i.e., left banks of the superior temporal sulcus, inferior temporal
gyrus, middle temporal gyrus, and superior temporal gyrus grey
matter volume), as well as frontal and parietal cortical regions that
have been shown to associate with episodic memory performance,
specifically the left middle frontal (i.e., left caudal and rostral mid-
dle frontal gyri grey matter volume), left lateral frontal (i.e., left
pars opercularis, pars orbitalis, and pars triangularis gyri grey mat-
ter volume) and left parietal neocortex (left inferior parietal, supe-
rior parietal, and supramarginal grey matter volume) (Kramer
et al., 2005).
2.5. Statistical analysis
To evaluate group differences in episodic memory performance,
a repeated measures analyses of covariance was conducted for de-
layed recall and univariate analysis of covariance for recognition d0,
with alpha set a p = 0.05. For delayed recall, Trial 5 was included as
a repeated measure (i.e., Trial 5 vs. Short Delay Free Recall) in order
to account for differences in verbal learning. To assess the relation-
ship between inflammation and structural imaging variables
(including our region of interest: medial temporal lobe volume),
separate univariate analyses of covariance were conducted, con-
trolling for intracranial volume (ICV; i.e., head size). In terms of
general study covariates, several demographic and health/lifestyle
variables have been shown to affect the relationship between
inflammation and cognitive functioning, including gender and
cardiovascular risk factors (Ravaglia et al., 2005; Wersching et al.,
2010; Simen et al., 2011). Thus, the decision to control for specific
confounds was based on two factors. Covariates were included in
analyses if one of the following two criteria were met: a) signifi-
cant between-group (Detectable vs. Undetectable CRP) differences
or b) significant correlations with primary dependent variables
were found. Significance was leniently defined as p 6 0.1 to
account for all possible confounds. Based on this criteria, between
group differences were found for current tobacco use (p = 0.04),
Body Mass Index (BMI; p = 0.01), and history of hypertension
(p = 0.1); correlations with primary dependent variables were
found for age (CVLT recall: r = ?0.36, p < 0.01; medial temporal
lobe: age, r = ?0.30, p < 0.01), gender (CVLT recall: r = 0.26,
p < 0.01; medial temporal lobe: r = ?0.20, p < 0.05), and MMSE
(CVLT recall: r = 0.14, p = 0.10). Thus, the following covariates were
used for all analyses: age, gender, MMSE, BMI, current tobacco use,
and history of hypertension.
Additional demographic and health variables are reported in
Table 1, including use of non-aspirin non-steroidal anti-inflamma-
tory drugs (NSAID)1, aspirin, and statins, but were not related to
outcome variables and did not significantly differ between groups
(p’s > 0.1); as such, these variables were not controlled for in analy-
ses. In addition, several lifestyle and health covariates were available
only for a subsection of the sample (137 out of 141 participants for
memory measures; 129 out of 133 participants for imaging analy-
ses); as such, analyses are presented separately for variables avail-
able for all participants (age, gender, MMSE) vs. the subsection of
participants (BMI, current tobacco use, history of hypertension).
Fig. 1. Significant interaction between learning and delayed recall by CRP group
(detectable vs. undetectable). Error bars represent standard error of the mean, and
values are based on estimated marginal means.
1Non-aspirin NSAID use included the following self-reported medications:
diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,
ketorolac, meclofenamate, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, or
B.M. Bettcher et al./Brain, Behavior, and Immunity 26 (2012) 103–108
Effect sizes for all analyses were estimated using Cohen’s d calcula-
tions (Cohen, 1988).
3.1. Primary indices of episodic memory: delayed recall
After controlling for significant demographic covariates, there
was a significant Group ? Recall trial interaction (F(1, 136) = 5.42,
p = 0.02; d = 0.56), such that participants with detectable levels of
CRP evidenced worse performance after a delay (Short Delay Free
Recall Mean = 10.7, SD = 3.3) compared to those with undetectable
levels of CRP (Mean = 12.0, SD = 3.1; see Fig. 1). After controlling
for all significant covariates, the Group ? Recall trial interaction re-
mained (F(1, 129) = 6.15, p = 0.01; d = 0.63).
3.2. Supplementary indices of episodic memory: recognition memory
After controlling for significant demographic covariates, partic-
ipants’ performance on a recognition trial revealed a significant
disparity in their ability to discriminate between target words
and foils (recognition d0: F (1136) = 4.11, p = 0.05; d = 0.35); specif-
ically, individuals with detectable levels of CRP performed worse
(recognition d0= 3.2, SD = 0.7) on this measure than those with
undetectable levels (recognition d0= 3.4, SD = 0.6), suggesting
poorer verbal recognition memory. The noted group differences
could not be accounted for by response bias (p = 0.54), and re-
mained even when controlling for all significant covariates
(p = 0.04; d = 0.38) and total learning on Trial 5 (p = 0.05; d = 0.36).
3.3. Inflammation and neuroimaging index of episodic memory
Univariate analysis of covariance revealed that participants
with detectable CRP had smaller left medial temporal lobes
(7.71 cc, SD = 0.7) than individuals with undetectable levels
(8.02 cc, SD = 0.8; F(1, 127) = 4.48, p = 0.04; d = 0.38), but no group
differences in left temporal neocortex (32.05 cc vs. 32.54 cc,
p = 0.29; d = 0.20), left middle frontal (20.22 cc vs. 20.21 cc,
p = 0.60; d = 0.10), left lateral frontal (9.71 cc vs. 9.66 cc, p = 0.81;
d = 0.05), or left parietal neocortex volume (45.20 cc vs. 45.80 cc,
p = 0.34; d = 0.15) were noted after controlling for significant
demographic covariates. Group differences in medial temporal
lobe volume remained after controlling for all significant covari-
ates (F(1, 120) = 4.87, p = 0.03; d = 0.42), with no changes in results
for left temporal neocortex, middle frontal gyrus, lateral gyrus, or
Our results indicate that functionally intact, neurologically
healthy older adults with detectable levels of the circulating
inflammatory marker, CRP, evidenced poorer verbal memory con-
solidation and smaller left medial temporal lobes. Within the con-
text of verbal episodic memory functioning, detectable levels of
CRP were related to lower performance on a delayed recall task
and a diminished ability to discriminate between target words
and foils on a recognition memory trial. Additionally, detectable
levels of CRP were associated with smaller left medial temporal
lobes, a neuroanatomic area known to buttress verbal episodic
memory consolidation. These group differences in neuroimaging
findings could not be better accounted for by left temporal neocor-
tex, left lateral or middle frontal grey matter volumes, or left pari-
etal neocortical volumes. Overall, these findings support our
hypotheses by associating inflammation with alterations in epi-
sodic memory function and brain structure.
The literature relating inflammatory biomarkers to cognitive
function has primarily emphasized the downstream effects of neu-
rodegenerative disease processes on postmortem evidence of
inflammation (e.g., activated microglia). Early postmortem evalua-
tions of Alzheimer’s disease patients identified increased inflam-
matory markers, including CRP, in the brain (McGeer and
McGeer, 1995), as well as immunoreactivity of CRP in neurofibril-
lary tangles (Duong et al., 1997), suggesting an inflammatory state.
Despite evidence that increased markers of inflammation predict
later cognitive decline (Weaver et al., 2002; Yaffe et al., 2004;
Dik et al., 2005; Alley et al., 2008), there is a dearth of research
examining the relationship between inflammation and cognitive
functioning in neurologically healthy older adults. In particular,
evidence linking laboratory markers of inflammation and episodic
memory have been contradictory (Dik et al., 2005; Wersching
et al., 2010), signifying a possibly tenuous relationship between
By contrast, the results of this study point to an association be-
tween episodic memory consolidation and recognition and a labo-
ratory marker ofinflammation.
incongruous findings in the past is that characterization of memory
in large samples is often cursory, with either one unitary score or
several different measures collapsed to reflect the multi-faceted
domain of verbal episodic memory. Given that neurologically
healthy older adults generally perform well on commonly used
composite indices of verbal memory, the more comprehensive ap-
praisal utilized in the current work may have unearthed subtle
changes in cognitive functioning not typically assessed in epidemi-
Pursuant to the discussion of episodic memory, verbal recall is a
heterogeneous construct consisting of several cognitive functions,
including executive control, attention, and processing speed, as
well as what we traditionally define as ‘memory’. As such, an
important consideration is whether the findings of the current
study reflect a consolidation (i.e., hippocampal dependent) vs. re-
trieval (i.e., dorsolateral frontal dependent) memory profile in the
detectable CRP group. Memory profiles typified by consolidation
difficulties are associated with poor free recall and minimal benefit
from a recognition trial (Delis et al., 1991; Kramer et al., 2005;
Price et al., 2009); in contrast, memory profiles typified by retrieval
difficulties are associated with relatively better verbal recall and
notable benefit from a recognition trial (Kramer et al., 1988; Lamar
et al., 2010). Our results provide preliminary support for a consol-
idation profile in the detectable CRP group based on the cognitive
data ascertained, as individuals with detectable levels of CRP dem-
onstrated a greater decline in performance on delayed recall (rela-
tive to learning trials) and worse performance on a recognition
memory trial, even after controlling for significant demographic,
medication, and cardiovascular variables. A consolidation profile
is further supported by the significant differences observed in
brain structure, as individuals with detectable levels of CRP dis-
played smaller left medial temporal lobe volumes, with no con-
comitant differences in left temporal neocortex, parietal, or
frontal lobe volumes. Of note, the participants in the current study
were healthy older adults, with no evidence of clinically significant
memory difficulties. Thus, this discussion is not to suggest that the
participants evidenced impairments in this domain. However, con-
sidering that mechanistically, inflammation is purported to affect
episodic memory by disrupting long-term potentiation in the med-
ial temporal lobe, the current results provide preliminary support
for an association between inflammation and a consolidation mem-
In evaluating the findings associating inflammation and mem-
ory function, it is important to highlight several salient consider-
ations and limitations. First, the relationship between peripheral
laboratory markers of inflammation and cognition is complex,
One explanationfor the
B.M. Bettcher et al./Brain, Behavior, and Immunity 26 (2012) 103–108
and is likely moderated by lifestyle variables, vascular risk factors,
and psychological functioning (e.g., stress, depression) (Black,
2002; Yaffe et al., 2004). Although we were able to incorporate
and control for several participant-reported indices of lifestyle
and cardiovascular risk, unearthing a linear, causal relationship be-
tween inflammation and memory function is complicated by our
limited understanding of how these factors interact and modify
each other. Although there is considerable evidence in animal
models suggesting that inflammation directly impacts hippocam-
pal functioning (Spulber and Schultzberg, 2010; Terrando et al.,
2010), it is also plausible that inflammation plays a secondary,
downstream role and is not necessarily the culpable factor driving
these noted changes (Luciano et al., 2009). Given that the temporal
relationship between elevations in inflammatory markers and cog-
nitive change remains unclear, caution should be applied when
attempting to make a causal association between the two. Second,
the mild changes in episodic memory functioning beg the question
of whether participants in the detectable CRP group are demon-
strating early changes due to a neurodegenerative disease process.
Given that the analyses were cross-sectional, it is currently unclear
whether these participants will progress to develop MCI or later a
dementia. However, while inflammation is clearly observed in neu-
rodegenerative diseases, it is not pathognomonic nor is it specific
in etiology. Mild changes in cognition do not necessarily suggest
evidence of a pre-clinical neurodegenerative disease; thus, while
we cannot definitively rule out an early, underlying process, all
participants presented as ‘‘normal’’ healthy controls, and were
screened for evidence of mild cognitive impairment or dementia.
Alternative, non-degenerative reasons for the observed differ-
ences in the inflammatory marker, cognition, and medial temporal
lobes include a low-grade, system wide response to the aging pro-
cess, acute inflammation, or vascular disease/risk factors not as-
sessedin the currentstudy.
individuals whose CRP levels fell below 3.0 mg/dL, a benchmark
for acute inflammation (Wersching et al., 2010), the range of values
still include those at the higher end of risk (detectable CRP range:
0.1–2.4 mg/dL) (Pearson et al., 2003); as such, we cannot defini-
tively rule out the contribution of underlying acute inflammation
in some of our patients. While this does not directly answer why
a large portion of our participants evidenced detectable levels of
CRP while others did not, our study does imply a relationship be-
tween inflammation and cognition in a relatively healthy, aging
population. Importantly, our study provides preliminary evidence
for specific changes in episodic memory and medial temporal lobe
volume that are supported in animal models (Terrando et al.,
Finally, it is also important to highlight that the current study is
cross-sectional in design and incorporated one commonly used
peripheral index of inflammation; thus, the findings cannot be gen-
eralized to issues related to cognitive decline or protracted inflam-
matory processes, nor can they address relations between other
inflammation analytes and cognitive functioning. Future studies
should focus on elucidating the temporal role of inflammatory
markers in aging and isolate modifiable factors that may confer
risk for accelerated and pathological cognitive aging. In particular,
longitudinal studies are crucial to our understanding of how
inflammatory markers, cognition, and brain structure may or
may not change in concert over time.
In summary, findings from the current study indicate that
healthy, community-dwelling older adults with detectable levels
of a peripheral inflammatory marker, C-reactive protein, demon-
strate worse verbal memory consolidation and recognition
memory, and smaller left medial temporal lobes than individuals
with undetectable levels of CRP. This study offers the first detailed
analysis of episodic memory function in relation to an inflamma-
tory marker and medial temporal lobe volume in older adults.
Although weonly included
These results highlight the utility of examining numerous indices
of memory when evaluating the role of inflammation in healthy
older adults, and underscore a potential role for inflammation in
The project described was supported by grant numbers P50
AG023501 and R01 AG032289 from NIH National Institute on
Aging. Its contents are solely the responsibility of the authors
and do not necessarily represent the official views of the National
Institute on Aging or NIH. This work was also supported by the Lar-
ry L. Hillblom Foundation, and an anonymous private foundation. A
portion of this work was presented at the 2011 American Academy
of Neurology meeting. Dr. Bettcher had full access to all the data in
the study and takes responsibility for the integrity of the data and
the accuracy of the data analysis. We would like to thank Dr.
Amanda K. LaMarre for her helpful comments on an earlier version
of this manuscript.
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