Slow gait, white matter characteristics, and prior 10-year interleukin-6 levels in older adults

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 (b 5 20.27, p , 0.001) and to higher WMH (b 5 0.23, p 5 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 5 0.043) in the mediation analyses.Conclusions: Sustained exposure to high IL-6 over 10 years rather than the rate of change in or an isolated high IL-6 level may adversely affect gait speed by influencing 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.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 longterm 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 studies [6][7][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.

Association of Neurocognitive and Physical Function With Gait Speed in Midlife

“…27 Slow gait was associated with the volume of white matter hyperintensities, which is associated with cognitive decline and dementia, 28 although this association diminished when we controlled for body composition or childhood SES. These findings in 45-year-old participants parallel those of studies 29,30 showing that gait speed is associated with structural brain changes in older adults and that total brain volume and white matter hyperintensities are associated with gait slowing in older adults. 31,32 indicator of good overall physical status because the brain is a sensitive organ and possibly the first to indicate weak overall somatic system integrity across multiple organ systems.…”

“…Slow gait was associated with the volume of white matter hyperintensities, which is associated with cognitive decline and dementia, although this association diminished when we controlled for body composition or childhood SES. These findings in 45-year-old participants parallel those of studies showing that gait speed is associated with structural brain changes in older adults and that total brain volume and white matter hyperintensities are associated with gait slowing in older adults . These findings survived correction for multiple testing applied within the brain structure domain, but if correction for multiple testing had been applied across all study measures simultaneously, only total brain volume would have remained associated with gait speed, suggesting that findings for cortical thickness, surface area, and white matter hyperintensities, although consistent with the literature, should be treated with caution.…”

A population neuroscience approach to the study of cerebral small vessel disease in midlife and late life: an invited review

“…The state of the evidence is strongest for a positive association of inflammatory factors with WMH. Both C-reactive protein and IL-6 have been found to be related to WMHs (92,112), but overall study results are mixed (3,83,92,112,118,120,140). Cumulative exposure, longer duration of exposure, and variability over time in the levels of these factors all appear to be important, but few studies have examined these characteristics concurrently.…”

Systemic Inflammation Mediates Age-Related Cognitive Deficits

“…These associations between systemic inflammation and cognitive impairment have been found in young (Brydon et al, 2008 ), middle-aged (Marsland et al, 2008 , 2015 ), and older (Athilingam et al, 2013 ; Tegeler et al, 2016 ) adults. Furthermore, within older adults, this inflammation−cognition link has been documented among generally healthy individuals (Brydon et al, 2008 ; Heringa et al, 2014 ; Nadkarni et al, 2016 ; Tegeler et al, 2016 ) and in clinical samples with conditions like dementia (Trollor et al, 2010 ), heart failure (Athilingam et al, 2013 ) and late-life depression (Charlton et al, 2018 ). However, to our knowledge, previous studies have not directly examined the mediatory role of systemic inflammation on cognitive aging.…”