Are BMI and inflammatory markers independently associated with physical fatigability in old age?

BACKGROUND: Obesity and chronic low-grade inflammation have both been implicated in the onset of physical fatigue. However, few studies have investigated the independence of these associations in older community-dwelling populations. We therefore aimed to investigate the associations of body mass index (BMI) and inflammatory markers at age 60-64 with perceived physical fatigability at age 68 and to assess whether any such associations were independent of each other and potential confounding factors. A secondary aim was to investigate whether any association with BMI extended back into earlier adulthood. METHODS: Participants of the MRC National Survey of Health and Development (N = 1580) had BMI and levels of interleukin-6 (IL-6) and C-reactive protein (CRP) measured during clinical assessments at age 60-64. These were related to self-perceived physical fatigability assessed at age 68 using the Pittsburgh Fatigability Scale (PFS) (total score:0 (no physical fatigue)-50 (extreme physical fatigue)). RESUTS: Women had higher mean PFS scores than men (mean (SD): 16.0 (9.1) vs 13.2 (8.9), p < 0.01). In sex-adjusted models, BMI, CRP and IL-6 were each associated with PFS scores. When all three factors were included in the same model, BMI and IL-6 remained associated with PFS scores whereas CRP did not. After adjustment for a range of potential confounders, associations of BMI and IL-6 with PFS scores were still evident; fully adjusted differences in mean PFS score = 3.41 (95% CI: 0.59, 6.24) and 1.65 (0.46, 2.84) for underweight and obese participants when compared with normal weight and, 2.78 (1.65, 3.91) when comparing those with an IL-6 of 2.51-8.49 pg/mL with levels <1.50. CONCLUSIONS: BMI and inflammation may both be suitable targets for intervention to reduce the burden of physical fatigability in later life. Further, interventions that target both obesity and elevated levels of IL-6 are likely to be more effective than those focusing on only one.

The MRC National Survey of Health and Development reaches age 70: maintaining participation at older ages in a birth cohort study.

A life course approach to ageing relies on maintaining participation rates in national birth cohorts and other long-term longitudinal studies. This reduces the risk of selective attrition biasing associations between lifetime risk factors and health outcomes in later life and ensures the studies remain as representative as possible of the original population. We report the participation patterns for a postal questionnaire and home visit at 68-69 years of study members in the MRC National Survey of Health and Development, the oldest and longest-running British birth cohort study. We investigated how participation varied by lifetime and recent contact, health status, previous clinical feedback and study engagement, taking account of prior socioeconomic and cognitive characteristics. Overall participation and home visit participation remained high (94 and 80%, respectively) and there were no gender differences. Participation was higher in those with higher levels of prior contact and lower in those with the poorest health status. Having previously received clinical feedback on actionable blood results was associated with reduced home visit participation but other forms of clinical feedback were not associated with subsequent participation. Activities that fostered study engagement were associated with increased home visit participation. These findings inform strategies to maintain participation in life course studies.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.

Comparison of devices used to measure blood pressure, grip strength and lung function: A randomised cross-over study.

BACKGROUND: Blood pressure, grip strength and lung function are frequently assessed in longitudinal population studies, but the measurement devices used differ between studies and within studies over time. We aimed to compare measurements ascertained from different commonly used devices. METHODS: We used a randomised cross-over study. Participants were 118 men and women aged 45-74 years whose blood pressure, grip strength and lung function were assessed using two sphygmomanometers (Omron 705-CP and Omron HEM-907), four handheld dynamometers (Jamar Hydraulic, Jamar Plus+ Digital, Nottingham Electronic and Smedley) and two spirometers (Micro Medical Plus turbine and ndd Easy on-PC ultrasonic flow-sensor) with multiple measurements taken on each device. Mean differences between pairs of devices were estimated along with limits of agreement from Bland-Altman plots. Sensitivity analyses were carried out using alternative exclusion criteria and summary measures, and using multilevel models to estimate mean differences. RESULTS: The mean difference between sphygmomanometers was 3.9mmHg for systolic blood pressure (95% Confidence Interval (CI):2.5,5.2) and 1.4mmHg for diastolic blood pressure (95% CI:0.3,2.4), with the Omron HEM-907 measuring higher. For maximum grip strength, the mean difference when either one of the electronic dynamometers was compared with either the hydraulic or spring-gauge device was 4-5kg, with the electronic devices measuring higher. The differences were small when comparing the two electronic devices (difference = 0.3kg, 95% CI:-0.9,1.4), and when comparing the hydraulic and spring-gauge devices (difference = 0.2kg, 95% CI:-0.8,1.3). In all cases limits of agreement were wide. The mean difference in FEV1 between spirometers was close to zero (95% CI:-0.03,0.03), limits of agreement were reasonably narrow, but a difference of 0.47l was observed for FVC (95% CI:0.53,0.42), with the ndd Easy on-PC measuring higher. CONCLUSION: Our study highlights potentially important differences in measurement of key functions when different devices are used. These differences need to be considered when interpreting results from modelling intra-individual changes in function and when carrying out cross-study comparisons, and sensitivity analyses using correction factors may be helpful.

Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study.

OBJECTIVE: Low back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population. MATERIAL AND METHODS: A cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18-84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition. RESULTS: The major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (p<0.001) associated with non-specific LBP. The single most important risk factor was the amount of LDD. After adjustment for other risk factors, the individuals who exhibited advanced LDD (90% vs 10%) had 3.2 higher odds of manifesting LBP. The data also showed a significant (p<0.001) genetic correlation between the LBP and LDD measurements, suggesting that approximately 11-13% of the genetic effects are shared by LDD and LBP. CONCLUSIONS: The main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.

Progression of lumbar disc degeneration over a decade: a heritability study.

OBJECTIVES: Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Cross-sectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors. METHODS: A 10-year follow-up of MRI-determined LDD was performed in 234 pairs of twin volunteers in the UK and Australia, comprising 90 monozygotic pairs and 144 dizygotic same-sex twin pairs. Of the total sample, 95% were female. The mean age at baseline was 53.3 years (range 32.3-69.5). The rate of progression was calculated and, because the effect of age was non-linear, the sample was divided into age strata and heritability estimated for each trait's progression. RESULTS: All MRI-determined traits worsened significantly over the period of follow-up (p<0.0001 for each). Change in disc height was not heritable at any age while posterior disc bulge was heritable across all age categories (range 28-53%), with higher heritability in those over 60 years. Change in disc signal intensity and anterior osteophytes were found to be heritable only in those aged under 50 years at baseline (heritability estimates 76% (95% CI 44% to 100%) and 74% (42% to 100%), respectively). CONCLUSIONS: Longitudinal change in LDD traits is heritable for all traits except disc height, but there is a significant influence of age, which varies across traits. Future studies to define the genetic variants influencing LDD progression should examine MRI traits individually and in women should focus on those under 50 years of age.

Evidence that bone mineral density plays a role in degenerative disc disease: the UK Twin Spine study.

OBJECTIVE: Osteoarthritis (OA) and osteoporosis are often considered to lie at opposite ends of a spectrum of bone phenotypes. Lumbar degenerative disc disease (LDD) may be associated with low back pain (LBP) and is similar in many ways to OA. LDD is reported in small studies to be associated with increased spine bone mineral density (BMD). The present work aimed to confirm this association in a large population sample using MRI and explore the relationship further, in particular to determine whether it is mediated genetically. METHODS: A population based sample (N = 908, age range 32-74 years) of UK female twins having MRI of the lumbar spine was used in this study. LDD traits and summary measures and their relationship with BMD at the lumbar spine and hip were examined using multivariate multiple regression and maximum likelihood based variance decomposition. RESULTS: There was a significant positive correlation between LDD and BMD at the lumbar spine and hip, which remained significant after adjustment for confounders. Both traits were highly heritable and the associations between them were mediated genetically. CONCLUSIONS: A clear, significant and independent association of BMD at hip and lumbar spine with LDD was found which is, in part, genetically mediated. The association with the non-axial site, the hip, is of particular interest and suggests a systemic bone effect. This should encourage the search for pleiotropic genes to help in the understanding of the bone-cartilage relationship. Moreover, genetic variants identified could provide novel therapeutic targets in the management of LBP.

Imaging biomarkers of spine osteoarthritis.

While there is an acknowledged need for biomarkers to progress arthritis research, imaging biomarkers for the spine have lagged behind those for peripheral joint osteoarthritis. Progress has been slow for a number of reasons. First and perhaps most importantly, there is currently no international agreement on definition of spine osteoarthritis (OA), either histologically or on imaging. Secondly, spine OA comprises two main pathologies, and debate continues as to whether they are separate entities or linked: degenerative disc disease and facet joint arthritis. Imaging those neighbouring joints is not straightforward and usually requires separate imaging investigations. Thirdly, it is only just becoming clear to what extent changes on imaging are associated with the main clinical problem - back pain. To compound the problem, the organisation of clinical services usually means that different specialties tend to focus on different anatomical areas, so a combined approach is not commonly adopted. Systematic evaluation of facet joints in epidemiological study is still in its infancy. Regardless of these hurdles, we have attempted in this review to summarise the state of play of imaging biomarkers in the spine with the emphasis on degenerative disc disease. MR imaging clearly leads the way and there exists a variety of specialist techniques such as T1rho and which may offer spine research imaging biomarkers in the future.

The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features.

STUDY DESIGN: Cross-sectional open population based study (nested in a prospective cohort study). OBJECTIVE: To explore the association of the different individual radiographic features, including osteophytes and disc space narrowing, with self-reported low back pain (LBP). Different definitions of lumbar disc degeneration with self-reported LBP and disability were considered in a large open population sample. Furthermore, in order to disentangle the discrepancies in reported strength of the associations, we characterized the frequency of the different individual radiographic features of lumbar disc degeneration and definitions of lumbar disc degeneration, as well as their association with LBP status, by age, gender, and vertebral level. SUMMARY OF BACKGROUND DATA: Currently within the literature, there have been no studies that have explored different definitions of lumbar disc degeneration and their association with LBP within one study sample. METHODS: The intervertebral disc spaces (L1/2 to L5-S1) were evaluated for the presence and severity of anterior osteophytes and disc space narrowing using a semiquantitative score (grade 0-3). Logistic regression was used to determine the association between these individual radiographic features of lumbar disc degeneration and different definitions of lumbar disc degeneration for LBP. RESULTS: Lumbar radiographs were scored for 1204 men, and 1615 women. Osteophytes were the most frequent radiographic feature observed, with men having the greatest frequency. Disc space narrowing was more frequent in women than men. Both radiographic features increased in frequency with age.Disc space narrowing appeared more strongly associated with LBP than osteophytes, especially in men (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 1.4-2.8). Disc space narrowing at 2 or more levels appeared more strongly associated with LBP than disc space narrowing at only 1 level (OR = 2.4; 95% CI: 1.6-3.4). After excluding level L5-S1, the strength of almost all associations increased. CONCLUSION: We are the first to report different possible lumbar disc degeneration definitions and their associations with LBP. Disc space narrowing at 2 or more levels appeared more strongly associated with LBP than other radiographic features, especially after excluding level L5-S1.