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Slow gait, white matter characteristics, and
prior 10-year interleukin-6 levels in older adults
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"high IL-6 levels over the prior 10 years is strongly related to slower gait.....Increased levels of inflammatory cytokines such as interleukin-6 (IL-6) are cross-sectionally and longitudinally associated with poor physical function in older adults.....Several anti-inflammatory and immune-modulatory therapies, including dietary and behavioral interventions, have potential efficacy in reducing low-grade chronic inflammation in aging"
"In this cohort of older adults with mean age of 83 years, sustained exposure to high IL-6 levels over the prior 10 years is strongly related to slower gait and this association is explained by higher WMH burden in the brain....This study suggests that higher sustained exposure to IL-6 over 10 years is associated with slower gait in older adults and this relationship is mediated by cerebral WMH.
......Increased levels of inflammatory cytokines such as interleukin-6 (IL-6) are cross-sectionally and longitudinally associated with poor physical function in older adults
The results of this study have important clinical relevance to age-related mobility decline. Several anti-inflammatory and immune-modulatory therapies, including dietary and behavioral interventions, have potential efficacy in reducing low-grade chronic inflammation in aging. Vascular risk factor modification can potentially mitigate chronically elevated IL-6 levels and potentially affect gait slowing in older adults.4 Our findings suggest that low IL-6 levels sustained over a long-term period may be more meaningful for maintaining WM health and gait speed in older adults.
We found that higher IL-6 at time of MRI was related to worse NAWM-FA but not to WMH, whereas sustained IL-6 levels were associated with WMH but not with NAWM-FA. In aging, WMH represent the aftermath of longstanding WM injury that begins with changes in NAWM.32 IL-6 influences inflammatory signaling leading to microglial sensitization33,34 and neuronal damage,35 which decreases the spatial restrictiveness within fibers, making them less anisotropic,12 leading to a lower NAWM-FA signal on DTI.12 Over time, cytokines increase blood-brain permeability enabling reactive gliosis,36 one of the pathologic hallmarks of WMH. Thus, the relationship between concurrent high IL-6 and low NAWM-FA may become blunted over time and high IL-6 sustained over a long-term period could influence downstream development of WMH. This reasoning, though speculative, may explain the lack of relationship between sustained IL-6 and NAWM-FA and between concurrent IL-6 and WMH."
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Slow gait, white matter characteristics, and prior 10-year interleukin-6 levels in older adults
Neurology Published Ahead of Print on October 19, 2016
Abstract
Objective: To examine the relationship between gait speed and prior 10 years interleukin-6 (IL-6) burden in older adults. We then assessed whether white matter characteristics influence this relationship.
Methods: In 179 community-dwelling older adults, gait speed was assessed on an automated walkway and serum IL-6 was assayed on ELISA. Concurrently, white matter characteristics were assessed on MRI by quantifying volume of white matter hyperintensities (WMH), a marker of small vessel disease, and normal-appearing white matter on fractional anisotropy (NAWM-FA), a marker of axonal integrity. IL-6 was assayed at regular intervals at gait assessment and over the prior 10 years and estimates of sustained 10-year IL-6 exposure and the rate of change in IL-6 over 10 years were obtained. Multivariate linear regressions were used to examine the relationships among sustained IL-6 exposure, rate of change in IL-6, gait speed, and white matter characteristics.
Results: In this sample (age 83 years, 58% female, 41% black, gait speed 0.9 m/s), higher sustained IL-6 levels, but not the rate of change in IL-6 or IL-6 at gait assessment, was significantly related to slower gait (β = -0.27, p < 0.001) and to higher WMH (β = 0.23, p = 0.002), but not NAWM-FA, withstanding covariate adjustments. WMH accounted for 30% attenuation in the relationship between higher sustained IL-6 levels and slower gait speed (p = 0.043) in the mediation analyses.
Conclusions: Sustained exposure to high IL-6 over 10 years rather than the rate of change in IL-6 or an isolated high IL-6 level may adversely affect gait speed by influencing cerebral WMH.
GLOSSARY
3 MS=modified Mini-Mental State Examination score;
BMI=body mass index;
DTI=diffusion tensor imaging;
FLAIR=fluid-attenuated inversion recovery;
Health ABC=Health Aging and Body Composition;
IL-6=interleukin-6;
NAWM=normal-appearing white matter;
NAWM-FA=fractional anisotropy of normal-appearing white matter;
WM=white matter;
WMH=white matter hyperintensities
Increased levels of inflammatory cytokines such as interleukin-6 (IL-6) are cross-sectionally and longitudinally associated with poor physical function in older adults. 1,-,5 IL-6 assayed at regular intervals over a long-term period may better capture sustained IL-6 exposure and rate of change rather than random assays spread apart over time. It is not known whether the sustained long-term exposure to IL-6 or rate of change in IL-6 contributes to the relationship between IL-6 and gait speed beyond a single concurrent indicator of inflammation.
Higher IL-6 is linked to greater volume of white matter hyperintensities (WMH) on MRI in most studies6,-,8 but not in all.9 WMH are related to slow gait in older adults.10,11 In regions that are free of WMH, which we refer to here as normal-appearing white matter (NAWM), subtle changes are detected on diffusion tensor imaging (DTI) as a reduction in fractional anisotropy of NAWM (NAWM-FA), denoting loss of myelin and astrogliosis at the microstructural level.12,13 Lower NAWM-FA is related to slow gait in elders14,15 as well as chronic inflammation in aging.16 The potential central mechanisms underlying long-term effects of IL-6 on gait slowing remain unknown.
We examined the independent relationships among the longitudinal measures of IL-6 burden, gait speed, and cerebral white matter (WM) characteristics and assessed whether WM characteristics influence these relationships in community-dwelling older adults. We hypothesized that sustained elevation of IL-6 over 10 years is associated with slow gait and this relationship is influenced by cerebral WM disease burden in the brain.
DISCUSSION
In this cohort of older adults with mean age of 83 years, sustained exposure to high IL-6 levels over the prior 10 years is strongly related to slower gait and this association is explained by higher WMH burden in the brain. Each participant had an IL-6 assay conducted at every timepoint of the study, culminating with a final assay at time of gait assessment and brain MRI. Hence, we were able to comprehensively characterize long-term IL-6 burden by measuring sustained IL-6 exposure over 10 years and by estimating the rate of change in IL-6 over this period. Among the measures we utilized to characterize IL-6 burden, we found that only sustained 10-year IL-6 exposure was robust enough to withstand several statistical adjustments, whereas rate of change in IL-6 over 10 years or IL-6 at gait assessment and MRI timepoint were not significant on their own, did not withstand statistical adjustments, or were not significant when accounted for each other in the model. This is the first report indicating that in community-dwelling older adults, higher sustained IL-6 exposure could be detrimental to gait speed, possibly mediated by higher WMH burden in the brain.
The association between IL-6 and mobility decline is frequent but not universal; a significant association between high IL-6 levels and subsequent mobility decline was observed in the Health ABC study,3,4 the Women's Health and Aging Study,30 and InCHIANTI,2 but not in the MacArthur studies of successful aging.31 The Cardiovascular Health Study All-Stars study (mean age 84.9 years, with a demographic that was similar to our study sample) examined association of IL-6 levels at 2 timepoints 9 years apart concurrent with assessment of physical and cognitive impairment; higher baseline IL-6 levels were more strongly associated with slow gait than change in IL-6 over the 2 timepoints.5 This study supports our findings on the lack of robust association between rate of change in IL-6 over 10 years and slow gait speed.
We found that higher IL-6 at time of MRI was related to worse NAWM-FA but not to WMH, whereas sustained IL-6 levels were associated with WMH but not with NAWM-FA. In aging, WMH represent the aftermath of longstanding WM injury that begins with changes in NAWM.32 IL-6 influences inflammatory signaling leading to microglial sensitization33,34 and neuronal damage,35 which decreases the spatial restrictiveness within fibers, making them less anisotropic,12 leading to a lower NAWM-FA signal on DTI.12 Over time, cytokines increase blood-brain permeability enabling reactive gliosis,36 one of the pathologic hallmarks of WMH. Thus, the relationship between concurrent high IL-6 and low NAWM-FA may become blunted over time and high IL-6 sustained over a long-term period could influence downstream development of WMH. This reasoning, though speculative, may explain the lack of relationship between sustained IL-6 and NAWM-FA and between concurrent IL-6 and WMH.
We also found that sustained exposure to high IL-6 level was associated with greater WMH in the corpus callosum, corticospinal tracts, inferior fronto-occipital fasciculi, and superior longitudinal fasciculi. WMH in these tracts can disrupt neural transmission, leading to gait slowing in older adults.10,11,37 Tracts that traverse large areas of watershed WM are more prone to WM injury and WMH.38 Recent evidence also suggests that inflammation influences corpus callosal changes.39,40 Therefore, we speculate that tracts such as the corpus callosum, corticospinal, and long association tracts are likely to bear the brunt of longstanding effects of sustained high inflammation. The attenuation of the relationship between IL-6 exposure and slow gait by WMH points to the regional vulnerability of WM and a compromised neural connectivity of gait driven by an inflammation-mediated pathophysiologic mechanism.
The results of this study have important clinical relevance to age-related mobility decline. Several anti-inflammatory and immune-modulatory therapies, including dietary and behavioral interventions, have potential efficacy in reducing low-grade chronic inflammation in aging. Vascular risk factor modification can potentially mitigate chronically elevated IL-6 levels and potentially affect gait slowing in older adults.4 Our findings suggest that low IL-6 levels sustained over a long-term period may be more meaningful for maintaining WM health and gait speed in older adults.
There are several strengths of this study. We studied participants who had IL-6 levels drawn at every timepoint over the 10-year period. Inclusion into study ascertained that those with mobility disability or impaired mobility were excluded. WM was assessed with both 3T MRI and DTI, which were obtained concurrent with gait speed assessment. The sample was also racially diverse. Finally, our analysis accounted for several confounders known to influence gait in older adults.
Certain limitations need to be considered. Our sample of older adults was likely robust based on MRI and study eligibility and may therefore differ from others who report on similar phenomena in terms of sensitivity of IL-6 assays across timepoints, and sources of bias due to survival, health status, functional status, or cognition. Then again, the finding that sustained high IL-6 levels over 10 years influence gait speed and that WM disease appears to be a key driver of this association in this selective sample is noteworthy. We did not study other inflammatory cytokines such as C-reactive protein that are also linked to mobility decline in aging because C-reactive protein levels were not obtained at the timepoint of brain MRI and gait assessment in the Health ABC study. Brain imaging was not performed at baseline in the study and therefore, we were unable to examine the longitudinal relationships between WMH accrual and the IL-6 measures.
This study suggests that higher sustained exposure to IL-6 over 10 years is associated with slower gait in older adults and this relationship is mediated by cerebral WMH.
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