Complex and Simple Clinical Reaction Times Are Associated with Gait, Balance, and Major Fall Injury in Older Subjects with Diabetic Peripheral Neuropathy.
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ABSTRACT: The aim of this work was to identify relationships between complex and simple clinical measures of reaction time (RTclin) and indicators of balance in older subjects with and without diabetic peripheral neuropathy (DPN).Prospective cohort design. Complex RTclin accuracy, simple RTclin latency, and their ratio were determined using a novel device in 42 subjects (mean ± SD age, 69.1 ± 8.3 yrs), 26 with DPN and 16 without. Dependent variables included unipedal stance time (UST), step width variability and range on an uneven surface, and major fall-related injury over 12 months.In the DPN subjects, the ratio of complex RTclin accuracy to simple RTclin latency was strongly associated with longer UST (R/P = 0.653/0.004), and decreased step width variability and range (R/P = -0.696/0.001 and -0.782/<0.001, respectively) on an uneven surface. Additionally, the 2 DPN subjects sustaining major injuries had lower complex RTclin accuracy:simple RTclin latency than those without.The ratio of complex RTclin accuracy:simple RTclin latency is a potent predictor of UST and frontal plane gait variability in response to perturbations and may predict major fall injury in older subjects with DPN. These short latency neurocognitive measures may compensate for lower limb neuromuscular impairments and provide a more comprehensive understanding of balance and fall risk.
Complex and Simple Clinical Reaction Times Are Associated with Gait, Balance, and Major Fall Injury in Older Subjects with Diabetic Peripheral Neuropathy.
American journal of physical medicine & rehabilitation 20170101 1
<h4>Objective</h4>The aim of this work was to identify relationships between complex and simple clinical measures of reaction time (RTclin) and indicators of balance in older subjects with and without diabetic peripheral neuropathy (DPN).<h4>Design</h4>Prospective cohort design. Complex RTclin accuracy, simple RTclin latency, and their ratio were determined using a novel device in 42 subjects (mean ± SD age, 69.1 ± 8.3 yrs), 26 with DPN and 16 without. Dependent variables included unipedal stanc ...[more]
Project description:BackgroundSensory peripheral neuropathy (PN) is associated with gait, balance problems and high fall risk. The walk2Wellness trial investigates effects of long-term, home-based daily use of a wearable sensory prosthesis on gait function, balance, quality of life and fall rates in PN patients. The device (Walkasins®, RxFunction Inc., MN, United States) partially substitutes lost nerve function related to plantar sensation providing directional tactile cues reflecting plantar pressure measurements during standing and walking. We tested the null hypothesis that the Functional Gait Assessment (FGA) score would remain unchanged after 10 weeks of use.MethodsParticipants had PN with lost plantar sensation, gait and balance problems, an FGA score < 23 (high fall risk), and ability to sense tactile stimuli above the ankle. Clinical outcomes included FGA, Gait Speed, Timed Up&Go (TUG) and 4-Stage Balance Test. Patient-reported outcomes included Activities-Specific Balance Confidence (ABC) scale, Vestibular Disorders Activities of Daily Living Scale, PROMIS participation and satisfaction scores, pain rating, and falls. Evaluations were performed at baseline and after 2, 6, and 10 weeks. Subjects were not made aware of changes in outcomes. No additional balance interventions were allowed.ResultsForty-five participants of 52 enrolled across four sites completed in-clinic assessments. FGA scores improved from 15.0 to 19.1 (p < 0.0001), normal and fast gait speed from 0.86 m/s to 0.95 m/s (p < 0.0001) and 1.24 m/s to 1.33 m/s (p = 0.002), respectively, and TUG from 13.8 s to 12.5 s (p = 0.012). Four-Stage Balance Test did not improve. Several patient-reported outcomes were normal at baseline and remained largely unchanged. Interestingly, subjects with baseline ABC scores lower than 67% (high fall risk cut-off) increased their ABC scores (49.9% to 59.3%, p = 0.01), whereas subjects with ABC scores above 67% showed a decrease (76.6% to 71.8%, p = 0.019). Subjects who reported falls in the prior 6 months (n = 25) showed a decrease in the number of fall-risk factors (5.1 to 4.3, p = 0.023) and a decrease in fall rate (13.8 to 7.4 falls/1000 days, p = 0.014). Four pre-study non-fallers (n = 20) fell during the 10 weeks.ConclusionA wearable sensory prosthesis presents a new way to treat gait and balance problems and manage falls in high fall-risk patients with PN.Trial registrationClinicalTrials.gov (#NCT03538756).
Project description:Background/objectivesPeripheral neuropathy is a common diabetes complication that can increase fall risk. Regarding fall risk, the impact of pain management using tricyclic antidepressants (TCAs) or γ-aminobutyric acid (GABA) analogs is unclear because these medications can also cause falls. This study investigates the impact of these drugs on fall and fracture risk in older diabetic peripheral neuropathy (DPN) patients.DesignHistorical cohort study with 1-to-1 propensity matching of TCA/GABA-analog users and nonusers.SettingNationally representative 5% Medicare sample between the years 2008 and 2010.ParticipantsAfter applying all selection criteria, 5,550 patients with prescription and 22,200 patients without prescription of TCAs/GABA-analogs were identified. Both patient groups were then stratified for fall history and matched based on propensity of receiving TCAs/GABA-analogs within each group.MeasurementsPatients were followed until the first incidence of fall or the first incidence of fracture during the follow-up period (for up to 5 years).ResultsAfter matching, users and nonusers were largely similar. After covariate adjustment, TCA/GABA-analog use was associated with a statistically significant increase in fall risk (adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI] = 1.03-1.20), but was not associated with fracture risk (adjusted HR = 1.09; 95% CI = 0.99-1.19) in the conventional analysis. Treating TCA/GABA-analog use as a time-dependent covariate resulted in statistically significant associations of TCA/GABA-analog use with both fall and fracture risk (HR = 1.26 [95% CI = 1.17-1.36]; and HR = 1.12 [95% CI = 1.02-1.24], respectively).ConclusionAmong older patients with DPN, GABA-analogs or TCAs increase fall risk and possibly fracture risk. Use of these medications is therefore a potentially modifiable risk factor for falls and fractures in this population.
Project description:Poor balance control and increased fall risk have been reported in people with diabetic peripheral neuropathy (DPN). Traditional body sway measures are unable to describe underlying postural control mechanism. In the current study, we used stabilogram diffusion analysis to examine the mechanism under which balance is altered in DPN patients under local-control (postural muscle control) and central-control (postural control using sensory cueing). DPN patients and healthy age-matched adults over 55 years performed two 15-second Romberg balance trials. Center of gravity sway was measured using a motion tracker system based on wearable inertial sensors, and used to derive body sway and local/central control balance parameters. Eighteen DPN patients (age = 65.4±7.6 years; BMI = 29.3±5.3 kg/m2) and 18 age-matched healthy controls (age = 69.8±2.9; BMI = 27.0±4.1 kg/m2) with no major mobility disorder were recruited. The rate of sway within local-control was significantly higher in the DPN group by 49% (healthy local-controlslope = 1.23±1.06×10-2 cm2/sec, P<0.01), which suggests a compromised local-control balance behavior in DPN patients. Unlike local-control, the rate of sway within central-control was 60% smaller in the DPN group (healthy central-controlslope-Log = 0.39±0.23, P<0.02), which suggests an adaptation mechanism to reduce the overall body sway in DPN patients. Interestingly, significant negative correlations were observed between central-control rate of sway with neuropathy severity (rPearson = 0.65-085, P<0.05) and the history of diabetes (rPearson = 0.58-071, P<0.05). Results suggest that in the lack of sensory feedback cueing, DPN participants were highly unstable compared to controls. However, as soon as they perceived the magnitude of sway using sensory feedback, they chose a high rigid postural control strategy, probably due to high concerns for fall, which may increase the energy cost during extended period of standing; the adaptation mechanism using sensory feedback depends on the level of neuropathy and the history of diabetes.
Project description:DNA methylation is an epigenetic mechanism important for the regulation of gene expression, which plays a vital role in the interaction between genetic and environmental factors. Aberrant epigenetic changes are implicated in the pathogenesis of diabetes and diabetic complications, but the role of DNA methylation in diabetic peripheral neuropathy (DPN) is not well understood. Therefore, our aim in this study was to explore the role of DNA methylation in the progression of DPN in type 2 diabetes. We compared genome-wide DNA methylation profiles of human sural nerve biopsies from subjects with stable or improving nerve fibre counts to biopsies from subjects with progressive loss of nerve fibres. Nerve fibre counts were determined by comparing myelinated nerve fibre densities between an initial and repeat biopsy separated by 52 weeks. Subjects with significant nerve regeneration (regenerators) and subjects with significant nerve degeneration (degenerators) represent the two extreme DPN phenotypes. Using reduced representation bisulfite sequencing, we identified 3,460 differentially methylated CpG dinucleotides between the two groups. The genes associated with differentially methylated CpGs were highly enriched in biological processes that have previously been implicated in DPN such as nervous system development, neuron development, and axon guidance, as well as glycerophospholipid metabolism and mitogen-activated protein kinase (MAPK) signalling. These findings are the first to provide a comprehensive analysis of DNA methylation profiling in human sural nerves of subjects with DPN and suggest that epigenetic regulation has an important role in the progression of this prevalent diabetic complication.
Project description:When relaxation towards an equilibrium or steady state is exponential at large times, one usually considers that the associated relaxation time ?, i.e. the inverse of the decay rate, is the longest characteristic time in the system. However, that need not be true, other times such as the lifetime of an infinitesimal perturbation can be much longer. In the present work, we demonstrate that this paradoxical property can arise even in quite simple systems such as a linear chain of reactions obeying mass action (MA) kinetics. By mathematical analysis of simple reaction networks, we pin-point the reason why the standard relaxation time does not provide relevant information on the potentially long transient times of typical infinitesimal perturbations. Overall, we consider four characteristic times and study their behaviour in both simple linear chains and in more complex reaction networks taken from the publicly available database 'Biomodels'. In all these systems, whether involving MA rates, Michaelis-Menten reversible kinetics, or phenomenological laws for reaction rates, we find that the characteristic times corresponding to lifetimes of tracers and of concentration perturbations can be significantly longer than ?.
Project description:In this work we present a group of theoretical models for reaction times arising from simple-choice task tests. In particular, we argue for the inclusion of a shifted version of the Gamma distribution as a theoretical model based on a mathematical result on first hitting times. We contrast the goodness-of-fit of those models with the Ex-Gaussian distribution, using data from recently published experiments. The evidence of the results obtained highlights the convenience of proposing theoretical models for reaction times instead of models acting exclusively as quantitative distribution measurements.
Project description:The chaperome constitutes a broad family of molecular chaperones and co-chaperones that facilitate the folding, refolding, and degradation of the proteome. Heat shock protein 90 (Hsp90) promotes the folding of numerous oncoproteins to aid survival of malignant phenotypes, and small molecule inhibitors of the Hsp90 chaperone complex offer a viable approach to treat certain cancers. One therapeutic attribute of this approach is the selectivity of these molecules to target high affinity oncogenic Hsp90 complexes present in tumor cells, which are absent in nontransformed cells. This selectivity has given rise to the idea that disease may contribute to forming a stress chaperome that is functionally distinct in its ability to interact with small molecule Hsp90 modulators. Consistent with this premise, modulating Hsp90 improves clinically relevant endpoints of diabetic peripheral neuropathy but has little impact in nondiabetic nerve. The concept of targeting the "diabetic chaperome" to treat diabetes and its complications is discussed.
Project description:BackgroundDecreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies.MethodsBiopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture.ResultsHistological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology.ConclusionDPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage).Clinical relevanceRestoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.
Project description:A 62-year-old man was diagnosed as IgA nephropathy. He had a pancreatic tumor operation 19 years ago and had a normal plasma glucose test every year. One month after the medication of prednisolone acetate was administered his fasting plasma glucose elevated to 7.1mmol/L while he manifested symptoms of thirst, frequent urination, and weight loss. Approximately 3 months after the steroids, he started complaining of numbness, weakness, and muscle cramp in his lower extremities, blood tests showed elevated plasma glucose and electromyography (EMG) revealed impairment of the peripheral nerves in the lower extremity, diabetic peripheral neuropathy was diagnosed. Mecobalamin and Acupuncture were employed and steroids were discontinued, 8 months later he recovered part of his strength and sensation. This case presents a specific adverse drug reaction of corticosteroids that causes diabetes mellitus and subsequently leads to peripheral neuropathy in an acute onset.
Project description:ObjectivePeople with diabetic peripheral neuropathy (DPN) have impaired gait and balance performance. The aim of this study is to investigate therapeutic effectiveness of mechanical stimulation through a wearable foot compression device equipped in a shoe insole on vibration perception, balance control and gait performance in people with DPN.MethodsUsing a single-arm 4-week intervention study design, we examined effectiveness of daily use of shoes equipped with the foot compression device (Footbeat™, AVEX, Grand Junction, CO, USA) on improving vibration perception threshold (VPTmax), skin perfusion pressure (SPP), ankle brachial index (ABI), lower extremities edema (circumferences in the calf and ankle), and motor performance (postural sway with eyes open and closed conditions, and gait performance during normal, dual-task and fast walking). Thirty people with type 2 diabetes and symptoms of PN completed the experimental protocol.ResultsImprovements in VPTmax (before = 27.4 V, after = 23.3 V, P = .007, d = 0.33, where d denotes effect size), center-of-mass sway in the mediolateral direction with both eyes open and closed conditions (before = 0.94 cm, after = 0.76 cm, P = .020, d = 0.47; before = 1.10 cm, after = 0.83 cm, P = .033, d = 0.66, respectively), and stride velocity for normal walking, dual-task walking and fast walking tasks (before = 0.87 m/s, after = 0.96 m/s, P = .017, d = 0.41; before = 0.75 m/s, after = 0.91 m/s, P = .001, d = 0.77; before = 1.10 m/s, after = 1.20 m/s, P = .043, d = 0.33, respectively) were found post treatment. There was no significant improvement in SPP, ABI, and circumferences in the calf and ankle.ConclusionsOur findings suggest the wearable foot compression device may be effective for reducing neuropathic symptoms and enhancing motor performances in people with DPN.