Associations of Musculoskeletal Pain With Mobility in Older Adults: Potential Cerebral Mechanisms.
ABSTRACT: Musculoskeletal pain is highly prevalent and limits mobility in older adults. A potential mechanism by which pain affects mobility could be through its negative impact on the brain. We examined whether structural integrity of cerebral gray and white matter (WM) mediated the relationship between pain and mobility in community-dwelling older adults.Musculoskeletal pain, gait speed, and neuroimaging data were obtained concurrently from the Health ABC study (mean age = 83/56% female, n = 212). Microstructural gray matter integrity was measured by mean diffusivity (MD), WM microstructure and macrostructure were measured by fractional anisotropy (FA) and WM hyperintensities (WMH), respectively. Regression models were adjusted for gray matter atrophy, age, gender, medication use, and obesity. Bootstrapped mediation methods were used (1,000 bootstrapped samples, 95% confidence intervals).The associations of musculoskeletal pain with WMH (? = .19, p < .05) and FA (? = -.18, p < .05) were robust to adjustment for gender, medication use, age, body mass index (BMI), and brain atrophy. Participants who experienced both knee and back pain had a significantly slower gait speed (~0.11 m/s) than those without knee or back pain (p < .05) independent of gender, medication, age, and BMI. WMH and FA significantly mediated the pain-gait speed relationship. Associations between pain and MD were not significant, and MD did not modify the association between pain and gait speed.Cerebral WM integrity may contribute to the detrimental effects of musculoskeletal pain on mobility, although pre-existing WM integrity may also simultaneously amplify pain and decrease mobility. Future studies are needed to further understand whether successful pain management may significantly improve both brain health and mobility.
Project description:We examined the relationship among white matter (WM) tract integrity, WM hyperintensities (WMH), lobar gray matter (GM) volumes, and cognition in the cross-sectional Framingham Offspring Study. Six hundred eighty participants (71.7 ± 7.7 years) completed cognitive testing and magnetic resonance imaging. Diffusion tensor imaging probabilistic tractography was used to reconstruct major WM tracts. We computed tract-specific mean fractional anisotropy (FA) and tract-specific WMH ratio. Linear regressions identified relations between tracts and lobar GM volumes. Partial least squares regression examined associations between integrity of combined tracts, lobar GM volumes and cognition, including scores of memory and processing speed. Five tracts were particularly vulnerable to WMH, and tract-specific WMH volumes were inversely associated with tract-specific FA (p values < 0.05). Tract-specific FA related to lobar GM volumes. Memory was associated with lobar GM, while processing speed related to both tract integrity and lobar GM volumes. We conclude that subtle microstructural WM tract degeneration relates to specific lobar GM atrophy. The integrity of associated WM tracts and GM lobes differentially impacts memory and processing speed.
Project description:White matter hyperintensities (WMH), a common marker of cerebral small vessel disease, and lower microstructural integrity of normal-appearing white matter are associated with slower gait. How these cerebral measures interact in relation to slower gait is unknown. We assessed whether microstructural integrity of normal-appearing white matter, measured by fractional anisotropy (FA), moderates the association of higher WMH with slower gait.WMH, FA, and gait speed were acquired for 265 community-dwelling older adults (average age = 82.9 years).The inverse association between WMH and gait was robust to adjustment for age, gender, muscle strength, obesity, stroke, and hypertension (fully adjusted model: ?s = -0.19, p = .001). The interaction between WMH and FA was significant; analyses stratified by FA showed that the inverse association between WMH and gait speed was significant only for those with low FA (FA < median, fully adjusted model: ?s = -0.28, p = .001). Voxel-based results were similar for participants with FA less than median, there was an inverse association between gait speed and WMH which extended throughout the white matter (genu and body of corpus callosum, anterior limb of internal capsule, corona radiata, and superior longitudinal and fronto-occipital fasciculus). In contrast, for participants with FA ? median, the association was limited to the genu of corpus callosum, the cingulum, and the inferior longitudinal fasciculus.Microstructural integrity is a moderating factor in the association between WMH and gait. Future studies should examine whether higher microstructural integrity represents a source of compensation in those with greater WMH burden to maintain function in late life.
Project description:<h4>Objective</h4>To investigate the associations of Pittsburgh compound-B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults.<h4>Methods</h4>Cognitively unimpaired older adults from the population-based Mayo Clinic Study of Aging (<i>n</i> = 537, age 65-95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function <i>z</i>-scores were tested after adjusting for age and global cortical PiB SUVr.<h4>Results</h4>The WMH PiB SUVr was lower than NAWM PiB SUVr (<i>P</i> < 0.001). In the WMH, lower PiB SUVr correlated with lower FA (<i>r</i> = 0.21, <i>P</i> < 0.001), and higher MD (<i>r</i> = -0.31, <i>P</i> < 0.001). In the NAWM, lower PiB SUVr only correlated with higher MD (<i>r</i> = -0.10, <i>P</i> = 0.02). Both in the WMH and NAWM, lower PiB SUVr was associated with lower memory, language, and global cognitive function <i>z</i>-scores after adjusting for age and global cortical PiB SUVr.<h4>Interpretation</h4>Reduced PiB uptake in the WMH is associated with a loss of WM integrity and cognitive function after accounting for the global cortical PiB uptake, suggesting that WM PiB uptake may be an early biomarker of WM integrity that precedes cognitive impairment in older adults. When using WM as a reference region in cross-sectional analysis of PiB SUVr, individual variability in WMH volume as well as age should be considered.
Project description:BACKGROUND AND PURPOSE:Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid-femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts. METHODS:In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses. RESULTS:CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040; P<0.001, and a'=0.020; P>0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=-0.092; P<0.001, and b'=0.012; P>0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246; P<0.001, and c'=0.116; P>0.05). CONCLUSIONS:From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.
Project description:Age-related mobility limitations are debilitating and common. Cerebral white matter hyperintensities (WMH) and conditions affecting other systems are known contributors, but have been studied in isolation.In 2,703 adults aged 65 years or older, we assessed cross-sectional and longitudinal gait speed and mobility disability (self-reported difficulty walking half mile) in those with and without high burden of MRI-defined WMH along with six other conditions (OCs) affecting mobility: gender-specific weak grip; poor self-reported vision; gender-specific lowest quartile of forced vital capacity; self-reported joint pain; ankle-arm index less than 0.9; and body mass index (BMI) greater than 30 kg/m2. Separate regression models adjusted for age, gender, and race were repeated for each OC and based on a 4-level predictor: -WMH/-OC; -WMH/+OC; +WMH/-OC; and +WMH/+OC.Gait speed was fastest in those with -WMH/-OC and slowest for those with +WMH/+OC. Gait speed was similar for either WMH or one of the OC (p range: .07-.9), except for BMI. Those with a high BMI had slower gait speed than those with WMH (p = .01). Declines in gait speed over 6 years were similar for all groups. Results for both prevalent and incident mobility disability showed that associations for WMH and OC were similar for weak grip, poor vision, and low forced vital capacity (p range: .1-.7). Having joint pain, low ankle-arm index, or high BMI was associated with higher prevalent and incident mobility disability compared with having WMH (p range: <.001-.02).Cerebral WMH should be considered along with conditions affecting mobility from other systems when considering risk and treatment for mobility limitations.
Project description:Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ?75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.
Project description: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.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.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 (? = -0.27, p < 0.001) and to higher WMH (? = 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.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.
Project description:BACKGROUND:Diffusion-weighted imaging (DWI) has been widely used to investigate the integrity of white matter (WM; indexed by fractional anisotropy [FA]) in alcohol dependence and cigarette smoking. These disorders are highly comorbid, yet cigarette use has often not been adequately controlled in neuroimaging studies of alcohol-dependent populations. In addition, information on WM deficits in currently drinking, nontreatment-seeking (NTS) individuals with alcohol dependence is limited. Therefore, the aim of this work was to investigate WM microstructural integrity in alcohol use disorder by comparing matched samples of cigarette smoking NTS and social drinkers (SD). METHODS:Thirty-eight smoking NTS and 19 smoking SD subjects underwent DWI as well as structural magnetic resonance imaging. After an in-house preprocessing of the DWI data, FA images were analyzed with tract-based spatial statistics (TBSS). FA obtained from the TBSS skeleton was tested for correlation with recent alcohol consumption. RESULTS:Smoking NTS had lower FA relative to smoking SD, predominantly in the left hemisphere (p < 0.05, family-wise error rate corrected across FA skeleton). Across the full sample, FA and number of drinks per week were negatively related (? = -0.348, p = 0.008). Qualitative analyses of the structural connections through compromised WM as identified by TBSS showed differential connectivity of gray matter in NTS compared to SD subjects of left frontal, temporal, and parietal regions. CONCLUSIONS:NTS subjects had lower WM FA than SD, indicating compromised WM integrity in the NTS population. The inverse relationship of entire WM skeleton FA with self-reported alcohol consumption supports previous evidence of a continuum of detrimental effects of alcohol consumption on WM. These results provide additional evidence that alcohol dependence is associated with reduced WM integrity in currently drinking NTS alcohol-dependent individuals, after controlling for the key variable of cigarette smoking.
Project description:We investigated corticospinal tract (CST) integrity in the absence of white matter (WM) lesions using diffusion tensor imaging (DTI) in early MS disease stages.Our study comprised 19 patients with clinically isolated syndrome (CIS), 11 patients with relapsing-remitting MS (RRMS), and 32 age- and sex-matched healthy controls, for whom MRI measures of CST integrity (fractional anisotropy [FA], mean diffusivity [MD]), T1- and T2-based lesion load, and brain volumes were available. The mean (SD) disease duration was 3.5 (2.1) months, and disability score was low (median Expanded Disability Status Scale 1.5) at the time of the study.Patients with CIS and RRMS had significantly lower CST FA and higher CST MD values compared with controls. These findings were present, irrespective of whether WM lesions affected the CST. However, no group differences in the overall gray or WM volume were identified.In early MS disease stages, CST integrity is already affected in the absence of WM lesions or brain atrophy.
Project description:The neuroprotective effects of physical activity (PA) are consistently shown in older adults, but the neural substrates, particularly in white matter (WM), are understudied, especially in very old adults with the fastest growth rate and the highest risk of dementia. This study quantified the association between PA and WM integrity in adults over 80. The moderating effects of cardiometabolic conditions, physical functional limitations and WM hyperintensities were also examined, as they can affect PA and brain integrity. Fractional anisotropy (FA) from normal-appearing WM via diffusion tensor imaging and WM hyperintensities were obtained in 90 participants (mean age = 87.4, 51.1% female, 55.6% white) with concurrent objective measures of steps, active energy expenditure (AEE in kcal), duration (min), and intensity (metabolic equivalents, METs) via SenseWear Armband. Clinical adjudication of cognitive status, prevalence of stroke and diabetes, systolic blood pressure, and gait speed were assessed at time of neuroimaging. Participants were on average sedentary (mean ± SD/day: 1766 ± 1345 steps, 202 ± 311 kcal, 211 ± 39 min, 1.8 ± 1.1 METs). Higher steps, AEE and duration, but not intensity, were significantly associated with higher FA. Associations were localized in frontal and temporal areas. Moderating effects of cardiometabolic conditions, physical functional limitations, and WM hyperintensities were not significant. Neither FA nor PA was related to cognitive status. Older adults with a sedentary lifestyle and a wide range of cardiometabolic conditions and physical functional limitations, displayed higher WM integrity in relation to higher PA. Studies of very old adults to quantify the role of PA in reducing dementia burden via WM integrity are warranted.