Our results indicate that functionally intact, neurologically healthy older adults with detectable levels of the circulating inflammatory marker, CRP, evidenced poorer verbal memory consolidation and smaller left medial temporal lobes. Within the context 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 neocortex, left lateral or middle frontal grey matter volumes, or left parietal neocortical volumes. Overall, these findings support our hypotheses by associating inflammation with alterations in episodic memory function and brain structure.
The literature relating inflammatory biomarkers to cognitive function has primarily emphasized the downstream effects of neurodegenerative disease processes on postmortem evidence of inflammation (e.g. activated microglia). Early postmortem evaluations of Alzheimer’s disease patients identified increased inflammatory markers, including CRP, in the brain (McGeer and McGeer, 1995
), as well as immunoreactivity of CRP in neurofibrillary 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 the two.
By contrast, the results of this study point to an association between episodic memory consolidation and recognition and a laboratory marker of inflammation. One explanation for the 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 appraisal utilized in the current work may have unearthed subtle changes in cognitive functioning not typically assessed in epidemiological studies.
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. retrieval (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 consolidation profile in the detectable CRP group based on the cognitive data ascertained, as individuals with detectable levels of CRP demonstrated a greater decline in performance on delayed recall (relative 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 displayed smaller left medial temporal lobe volumes, with no concomitant 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, considering that mechanistically, inflammation is purported to affect episodic memory by disrupting long-term potentiation in the medial temporal lobe, the current results provide preliminary support for an association
between inflammation and a consolidation memory profile.
In evaluating the findings associating inflammation and memory function, it is important to highlight several salient considerations and limitations. First, the relationship between peripheral laboratory markers of inflammation and cognition is complex, 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 between 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 hippocampal 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 cognitive 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 demonstrating 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 neurodegenerative 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 differences in the inflammatory marker, cognition, and medial temporal lobes include a low-grade, system wide response to the aging process, acute inflammation, or vascular disease/risk factors not assessed in the current study. Although we only included 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: .1 to 2.4 mg/dL)(Pearson et al., 2003
); as such, we cannot definitively 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 between 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., 2010
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 generalized to issues related to cognitive decline or protracted inflammatory 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, demonstrate 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 inflammatory marker and medial temporal lobe volume in older adults. 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 cognitive aging.