Loss of lower extremity bone mineral density 1 year after denosumab is discontinued in persons with subacute spinal cord injury.

Twelve months following discontinuation of denosumab, the percent decrease in mean bone mineral density (BMD) values at the hip and knee regions were similar between both the denosumab and placebo groups. These findings emphasize the need for additional trials to understand the effect of continued administration of denosumab after subacute spinal cord injury (SCI) to avoid this demineralization. OBJECTIVE: To determine changes in BMD 1 year after denosumab was discontinued in participants with subacute SCI who had drug treatment initiated within 90 days post SCI and continued for 1 year. METHODS: Fourteen participants who completed a randomized, double-blinded, placebo-controlled drug trial (parent study: denosumab 60 mg (Prolia, Amgen Inc., n = 8) or placebo (n = 6); administered at baseline, 6, and 12 months) were followed 12 months after the 18 months from baseline primary end point was completed. The BMD of skeletal regions below the SCI at higher risk of fracture was measured [total hip, distal femur epiphysis (DFE), distal femur metaphysis (DFM), and proximal tibia epiphysis (PTE)] by dual energy X-ray absorptiometry. RESULTS: The percent decreases in mean BMD values at all regions of the hip and knee from 18 to 30 months were similar in both the denosumab and placebo groups. However, at 30 months, the absolute values for mean BMD remained significantly higher in the drug treatment than that of the placebo group at the DFM (p = 0.03), DFE (p = 0.04), and PTE (p = 0.05). CONCLUSIONS: In persons with SCI who initiated denosumab treatment during the subacute injury phase and maintained treatment for 1 year, the discontinuation of drug resulted in percent loss of mean BMD similar to that of the placebo group, with absolute mean BMD values at the knee regions at the 12-month follow-up visit significantly higher in the drug treatment than those in the placebo group. These data underscore the need to study continued administration of denosumab after subacute SCI to avoid marked demineralization in the sublesional skeleton upon discontinuation of this agent.

Generation of a Reference Dataset to Permit the Calculation of T-scores at the Distal Femur and Proximal Tibia in Persons with Spinal Cord Injury.

Persons with traumatic spinal cord injury (SCI) have severe bone loss below the level of lesion with the distal femur (DF) and proximal tibia (PT) being the skeletal regions having the highest risk of fracture. While a reference areal bone mineral density (aBMD) database is available at the total hip (TH) using the combined National Health and Nutrition Examination Survey (NHANES) III study and General Electric (GE) combined (GE/NHANES) to calculate T-score (T-scoreGE/NHANES), no such reference database exists for aBMD of the DF, and PT. The primary objectives of this study were (1) to create a reference dataset of young-healthy able-bodied (YHAB) persons to calculate T-score (T-scoreYHAB) values at the DF and PT, (2) to explore the impact of time since injury (TSI) on relative bone loss in the DF and PT regions using the two computation models to determine T-score values, and (3) to determine agreement between T-score values for a cohort of persons with SCI using the (T-scoreYHAB) and (T-scoreGE/NHANES) reference datasets. A cross-sectional prospective data collection study. A Department of Veterans Affairs Medical Center and a Private Rehabilitation Hospital. A normative reference aBMD database at the DF and PT was collected in 32 male and 32 female Caucasian YHAB participants (n=64) and then applied to calculate T-score values at the DF and PT in 105 SCI participants from a historical cohort. The SCI participants were then grouped based on TSI epochs (E-I: TSI < 1y, E-II: TSI 1-5y, E-III: TSI 6-10y, E-IV: TSI 11-20y, E-V: TSI > 20y). N/A. The knee and hip aBMD values were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA) using standard clinical software for proximal femur orthopedic knee software applications. There were no significant differences in mean aBMD values across the four YHAB age subgroups (21-25, 26-30, 31-35, and 36-40 yr of age) at the TH, DF, and PT; mean aBMD values were higher in men compared to the women at all skeletal regions of interest. Using the mean YHAB aBMD values to calculate T-score values at each TSI epoch for persons with SCI, T-score values decreased as a function of TSI, and they continued to decline for 11-20 yr. Moderate kappa agreement was noted between the YHAB and the GE/NHANES reference datasets for the T-score cutoff criteria accepted to diagnose osteoporosis (i.e., SD <-2.5). A homogeneous reference dataset of YHAB aBMD values at the DF and PT was applied to calculate T-score values in persons with chronic SCI. There was a moderate level of agreement at the TH between the YHAB and GE/NHANES reference datasets when applying the conventional T-score cutoff value for the diagnosis of osteoporosis.

The preliminary effects of moderate aerobic training on cognitive function in people with TBI and significant memory impairment: a proof-of-concept randomized controlled trial.

This single-blinded RCT investigated cognitive effects of aerobic exercise in persons with TBI-related memory impairment. Five participants . were randomly assigned to 12-weeks of either supervised moderate intensity aerobic cycling or an active control. Outcome measures included neuropsychological assessments and structural neuroimaging (MRI,). The exercise group demonstrated greater improvements on auditory verbal learning (RAVLT; d=1.54) and processing speed (SDMT; d=1.58). The exercise group showed larger increases in volume of the left hippocampus (d=1.49) and right thalamus (d=1.44). These pilot data suggest that 12-weeks of moderate intensity aerobic cycling may improve memory and processing speed in those with TBI-related memory impairments.

Predicting Cardiometabolic Risk From Visceral Abdominal Adiposity in Persons With Chronic Spinal Cord Injury.

Persons with spinal cord injury (SCI) have increased adiposity that may predispose to cardiovascular disease compared to those who are able-bodied (AB). The purpose of this study was to determine the relationships between dual energy X-ray absorptiometry (DXA)-derived visceral adipose tissue (VAT) and biomarkers of lipid metabolism and insulin resistance in persons with chronic SCI. A prospective observational study in participants with chronic SCI and age- and gender-matched AB controls. The study was conducted at a Department of Veterans Affairs Medical Center and Private Rehabilitation Hospital. The quantification of DXA-derived VAT volume (VATvol) and blood-derived markers of lipid and carbohydrate metabolism were determined in 100 SCI and 51 AB men. The VATvol was acquired from a total body DXA scan and analyzed using iDXA enCore CoreScan software (GE Lunar). Blood samples were collected for the serum lipid profile and plasma and glucose concentrations, with the latter two values used to calculate a measure of insulin resistance. In the SCI and AB groups, VAT% was significantly correlated with most cardiometabolic biomarkers. The results of the binary logistic regression analysis revealed that participants who had a VATvol above the cutoff value of 1630 cm3 were 3.1-, 4.8-, 5.6-, 19.2-, and 16.7-times more likely to have high serum triglycerides (R2N= 0.09, p = 0.014), low serum high density lipoprotein cholesterol (R2N = 0.16, p < 0.001), HOMA2-IR (R2N = 0.18, p < 0.001), metabolic syndrome (R2N = 0.25, p < 0.001), and a 10-yr Framingham Risk Score ≥ 10% (R2N = 0.16, p = 0.001), respectively, when compared to participants below this VATvol cutoff value. Our findings reveal that persons with chronic SCI have a higher VATvol than that of AB controls, and VATvol correlates directly with biomarkers of lipid and carbohydrate metabolism that are strong predictors of cardiometabolic disorders.

Oxygen Uptake During Exoskeletal-Assisted Walking in Persons With Paraplegia.

OBJECTIVE: To determine the cardiometabolic demands associated with exoskeletal-assisted walking (EAW) in persons with paraplegia. This study will further examine if training in the device for 60 sessions modifies cost of transport (CT). DESIGN: Prospective cohort study. Measurements over the course of a 60-session training program, approximately 20 sessions apart. SETTING: James J. Peters Bronx Veterans Affairs Medical Center, Center for the Medical Consequences of Spinal Cord Injury Research Center. PARTICIPANTS: The participants' demographics (N=5) were 37-61 years old, body mass index (calculated as weight in kilograms divided by height in meters squared) of 22.7-28.6, level of injury from T1-T11, and 2-14 years since injury. INTERVENTIONS: Powered EAW. MAIN OUTCOME MEASURES: Oxygen consumption per unit time (V˙O2, mL/min/kg), velocity (m/min), cost of transport (V˙O2/velocity), and rating of perceived exertion (RPE). RESULTS: With training: EAW velocity significantly improved (Pre: 51±51m; 0.14±0.14m/s vs Post: 99±42m; 0.28±0.12m/s, P=.023), RPE significantly decreased (Pre: 13±6 vs Post: 7±4, P=.001), V˙O2 significantly improved (Pre: 9.76±1.23 mL/kg/m vs Post: 12.73±2.30 mL/kg/m, P=.04), and CT was reduced from the early to the later stages of training (3.66±5.2 vs 0.87±0.85 mL/kg/m). CONCLUSIONS: The current study suggests that EAW training improves oxygen uptake efficiency and walking velocities, with a lower perception of exertion.

Effect of Exoskeletal-Assisted Walking on Soft Tissue Body Composition in Persons With Spinal Cord Injury.

OBJECTIVE: To determine the effect of overground walking using a powered exoskeleton on soft tissue body composition in persons with spinal cord injury (SCI). DESIGN: A prospective, single group observational pilot study. SETTING: Medical center. PARTICIPANTS: Persons (N=8) with chronic (>6mo) SCI between 18 and 65 years old who weighed less than 100 kg. INTERVENTIONS: Overground ambulation training using a powered exoskeleton (ReWalk) for 40 sessions, with each session lasting up to 2 hours, with participants training 3 times per week. MAIN OUTCOME MEASURE(S): Dual-energy x-ray absorptiometry (DXA) was used to measure lean mass (LM) and fat mass (FM) from the whole body, arms, legs and trunk. DXA was also used to assess visceral adipose tissue (VAT). Walking performance was measured by 6-minute walk test. RESULTS: Participants significantly lost total body FM (-1.8±1.2kg, P=.004) with the loss of adiposity distributed over several regional sites. Six of the 8 participants lost VAT, with the average loss in VAT trending toward significance (-0.141kg, P=.06). LM for the group was not significantly changed. CONCLUSIONS: Sustained and weekly use of powered exoskeletons in persons with SCI has the potential to reduce FM with inferred improvements in health.

Measurement of Visceral Adipose Tissue in Persons With Spinal Cord Injury by Magnetic Resonance Imaging and Dual X-Ray Absorptiometry: Generation and Application of a Predictive Equation.

PURPOSE: Dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) permits quantification of visceral adipose tissue (VAT). However, DXA has not been validated against MRI in persons with chronic spinal cord injury (SCI). A predictive equation was generated from the measurement of VAT by MRI, a "gold" standard to quantitate VAT, compared to that of DXA, a method with several practical advantages. METHOD: DXA and MRI scans were performed in 27 participants with SCI. MRI multiaxial images were captured for VAT analysis. DXA-VAT was quantified at the android region (DXA-VATANDROID-VOL) using enCore software. Android regions of DXA and MRI were matched using android height. Volumes of multiaxial MRI-VAT and subcutaneous adipose tissue (SAT) were quantified for the android region (MRI-VATANDROID-VOL, MRI-SATANDROID-VOL) and total trunk (MRI-VATANDROID-VOL). Linear regression analysis was used to establish the proposed predication equations. The prediction equations were then applied to an independent sample that consisted of 98 participants with SCI. Bland-Altman analysis was used to determine the limits of agreement. RESULTS: DXA-VATANDROID-VOL predicted 92% of the variance in MRI-VATANDROID-VOL (SEE = 252.5, p < 0.0005) and 85% of the variance in MRI-VATTRUNK-VOL (SEE = 1526.9, p < 0.0005). DXA-SATANDROID-VOL predicted 81.5% of the variance in MRI-SATANDROID-VOL (SEE = 458.2, p < 0.0005). Bland-Altman analysis revealed a high level of agreement between MRI-VATANDROID-VOL and DXA-VATANDROID-VOL (mean bias = 58.45 cm3). A predicted mean DXA-VATANDROID-VOL of 995.2 cm3 was estimated as the population-specific cut-off point for high levels of VAT. CONCLUSION: DXA-VATANDROID-VOL may accurately predict MRI-VATANDROID-VOL in persons with SCI. The ability of DXA to detect VAT changes in longitudinal studies in persons with SCI should be performed.

Bone Mineral Density Testing in Spinal Cord Injury: 2019 ISCD Official Position.

Spinal cord injury (SCI) causes rapid osteoporosis that is most severe below the level of injury. More than half of those with motor complete SCI will experience an osteoporotic fracture at some point following their injury, with most fractures occurring at the distal femur and proximal tibia. These fractures have devastating consequences, including delayed union or nonunion, cellulitis, skin breakdown, lower extremity amputation, and premature death. Maintaining skeletal integrity and preventing fractures is imperative following SCI to fully benefit from future advances in paralysis cure research and robotic-exoskeletons, brain computer interfaces and other evolving technologies. Clinical care has been previously limited by the lack of consensus derived guidelines or standards regarding dual-energy X-ray absorptiometry-based diagnosis of osteoporosis, fracture risk prediction, or monitoring response to therapies. The International Society of Clinical Densitometry convened a task force to establish Official Positions for bone density assessment by dual-energy X-ray absorptiometry in individuals with SCI of traumatic or nontraumatic etiology. This task force conducted a series of systematic reviews to guide the development of evidence-based position statements that were reviewed by an expert panel at the 2019 Position Development Conference in Kuala Lumpur, Malaysia. The resulting the International Society of Clinical Densitometry Official Positions are intended to inform clinical care and guide the diagnosis of osteoporosis as well as fracture risk management of osteoporosis following SCI.

Progressive Sublesional Bone Loss Extends into the Second Decade After Spinal Cord Injury.

OBJECTIVE: The rate of areal bone mineral density (aBMD) loss at the knee (distal femur (DF) and proximal tibia ) and hip (femoral neck (FN) and total hip (TH)) was determined in persons with traumatic spinal cord injury (SCI) who were stratified into subgroups based on time since injury (TSI). DESIGN: Cross-sectional retrospective review. SETTING: Department of Veterans Affairs Medical Center and Private Rehabilitation Hospital. PARTICIPANTS: Data on 105 individuals with SCI (TSI ≤12 months, n = 19; TSI 1-5 years, n = 35; 6-10 years, n = 19; TSI 11-20 years, n = 16; TSI >20 years, n = 15) and 17 able-bodied reference (ABref) controls. INTERVENTIONS: NA Main Outcome Measures: The knee and hip aBMD values were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA) using standard clinical software for the proximal femur employed in conjunction with proprietary research orthopedic knee software applications. Young-normal (T-score) and age-matched (Z-scores) standardized scores for the FN and TH were obtained using the combined GE Lunar/National Health and Nutrition Examination Survey (NHANES III) combined reference database. RESULTS: When groups were stratified and compared as epochs of TSI, significantly lower mean aBMD and reference scores were observed as TSI increased, despite similar mean ages of participants among the majority of TSI epoch subgroups. Loss in aBMD occurred at the distal femur (DF), proximal tibia (PT), FN, and TH with 46%, 49%, 32%, and 43% of the variance in loss, respectively, described by the exponential decay curves with a time to steady state (tss) occurring at 14.6, 11.3, 14, and 6.2 years, respectively, after SCI. CONCLUSIONS: Sublesional bone loss after SCI was marked and occurred as an inverse function of TSI. For aBMD at the hip and knee, tss extended into the second decade after SCI.

Estimates of the precision of regional and whole body composition by dual-energy x-ray absorptiometry in persons with chronic spinal cord injury.

STUDY DESIGN: Repeated measures design. OBJECTIVES: To determine the reproducibility of total-body and regional-body composition assessments from a total-body scan using dual-energy x-ray absorptiometry (DXA) in persons with spinal cord injury (SCI). METHODS: Twenty-four individuals with SCI completed within-day short-term precision testing by repositioning study participants between scans. An additional and separate cohort of 22 individuals with SCI were scanned twice on a GE-Lunar DXA scanner separated by a 4-week interval to assess the long-term precision assessment. The root mean square coefficient of variation percent (RMS-CV%) values for the regional and total body composition was calculated. RESULTS: For the same day, short-term precision assessment, the RMS-CV% for each region did not exceed 5.6, 2.7, 3.8, 6.5, 5.8, and 2.3% for arms, legs, trunk, android and gynoid regions, and total body mass, respectively. In the long-term precision assessment, the RMS-CV% for each region did not exceed 6.0, 3.0, 4.4, 8.2, 3.4, and 2.0% for arms, legs, trunk, android, gynoid, and total body mass. Moreover, the interclass-correlation coefficient in the long-term precision group demonstrated excellent linear agreement between repeat scans for all regions (r > 0.97). CONCLUSIONS: The precision error of the total body composition variables in our SCI cohort was similar to those reported in the literature for nondisabled individuals, and the precision errors of the regional body composition compartments were notably higher, but similar to the regional precision errors reported in the general population.

Administration of increasing doses of gonadotropin-releasing hormone in men with spinal cord injury to investigate dysfunction of the hypothalamic-pituitary-gonadal axis.

STUDY DESIGN: Prospective. OBJECTIVES: To determine the optimum gonadotropin-releasing hormone (GnRH) dose to identify dysfunction of the hypothalamic-pituitary-gonadal axis in men with spinal cord injury (SCI). SETTING: Metropolitan Area Hospitals, New York and New Jersey, USA. METHODS: SCI men (16 hypogonadal (HG = serum testosterone <12.1 nmol/l) and 14 eugonadal (EG)) and able-bodied (AB) men (27 HG and 11 EG) were studied. GnRH (10, 50, and 100 µg) was randomly administered intravenously on three separate visits. Blood samples were collected post-GnRH for serum-luteinizing hormone (LH) and follicular-stimulating hormone (FSH). RESULTS: HG and EG men had a similar proportion of clinically acceptable gonadotropin responses to all three GnRH doses. The incremental gonadotropin responses to GnRH were not significantly different across the groups. However, in the SCI-HG group, GnRH of 100 µg resulted in the greatest integrated FSH response, and in the SCI-EG group, GnRH of 50 µg resulted in the greatest integrated LH response compared with the AB groups. A consistent, but not significant, absolute increase in gonadotropin release was observed in the SCI groups at all GnRH doses. CONCLUSIONS: Lower doses of GnRH did not improve the ability to identify the clinical dysfunction of the hypothalamic-pituitary-gonadal axis. However, the absolutely higher SCI-HG FSH response to GnRH of 100 µg and a higher SCI-EG LH response to GnRH of 50 µg, along with a higher gonadotropin release at all GnRH doses, albeit not significant, suggests a hypothalamic-pituitary dysfunction in persons with SCI.

Establishing a threshold to predict risk of cardiovascular disease from the serum triglyceride and high-density lipoprotein concentrations in persons with spinal cord injury.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: This report identified the serum triglyceride (TG) concentrations in persons with spinal cord injury (SCI) and able-bodied (AB) individuals that the serum high-density lipoprotein cholesterol (HDL-C) equaled 40 mg/dl, a concentration below which is an independent risk factor for coronary artery disease. METHODS: Retrospective analysis was performed on 578 participants: 223 with SCI at or proximal to the 4th thoracic vertebrae (↑T4), 178 with SCI at or distal to the 5th thoracic vertebrae (↓T5), and 177 AB. Different statistical modeling approaches identified the intersecting serum TG concentration with a serum HDL-C concentration equal to 40 mg/dl. Participants were dichotomized into subgroups by TG concentration exceeding (supra) or falling below (sub) the intersecting value and the TG/HDL-C ratios were compared. RESULTS: Linear regression analysis revealed that the serum TG concentration that intersects with serum HDL-C concentration at 40 mg/dl was 121 mg/dl in SCI ↑T4 and 137 mg/dl in SCI ↓T5 group. A ROC curve identified the optimal TG concentration as 115 mg/dl in SCI ↑T4 and 137 mg/dl in SCI ↓T5 group with the latter concentration being similar to the AB group (e.g., 137 mg/dl). The TG/HDL-C ratios in the respective ↑T4, ↓T5, and AB supra and subgroups were similar within each group. CONCLUSIONS: A lower TG concentration appears to be associated with dyslipidemia in persons with SCI than AB individuals. These findings should prompt clinicians to screen for and consider instituting lifestyle or pharmacological interventions at lower TG concentrations to reduce risk of CVD.

Cutaneous microvascular perfusion responses to insulin iontophoresis are differentially affected by insulin resistance after spinal cord injury.

NEW FINDINGS: What is the central question of this study? What impact does insulin resistance have on cutaneous perfusion responses to insulin iontophoresis in vascular beds with markedly reduced or functionally ablated sympathetic nervous system vasomotor function resulting from spinal cord injury? What is the main finding and its importance? Persons with spinal cord injury have sublesional microvascular endothelial dysfunction, as indicated by a blunted cutaneous perfusion response to acetylcholine iontophoresis, and the presence of insulin resistance has a further confounding effect on endothelium-mediated changes to cutaneous perfusion in the lower extremities. Endothelium-mediated mechanisms that regulate skin blood flow might play an integral role in optimizing skin perfusion in vascular beds with sympathetic nervous system vasomotor impairment, such as in spinal cord injury (SCI). Insulin is a vasoactive hormone and second messenger of nitric oxide that facilitates endothelium-mediated dilatation. The effects of insulin resistance (IR) on sublesional cutaneous perfusion responses to insulin provocation have yet to be described in persons with SCI. Persons with SCI and an able-bodied (AB) cohort were divided into subgroups based upon fasting plasma insulin concentration cut-offs for IR (≥13.13 mIU ml-1 ) or insulin sensitivity (IS; <13.13 mIU ml-1 ), as follows: AB, IS (ABIS, n = 21); SCI, IS (SCIS, n = 21); AB, IR (ABIR, n = 9); and SCI, IR (SCIR, n = 11). Laser Doppler flowmetry characterized peak blood perfusion unit (BPU) responses (percentage change from baseline) to insulin, acetylcholine or placebo iontophoresis in the lower extremities; BPU responses were log10 transformed to facilitate comparisons, and the net insulin response (NetIns) BPU response was calculated (insulin minus placebo BPU response). The NetIns was significantly greater in both IS groups compared with their corresponding IR group. The acetylcholine-mediated BPU responses in the SCI subgroups were significantly lower than those in the ABIS group. The proportional BPU responses of NetIns to acetylcholine in the IS cohorts (i.e. ABIS and SCIS) were significantly greater (P < 0.05) than that of each IR subgroup. The presence of IR has a confounding effect on sublesional microvascular endothelium-mediated cutaneous perfusion responses to provocation. Preservation of endothelial sensitivity to its agonists appears to be an important modifiable risk factor to optimize cutaneous perfusion in the lower extremities of persons with SCI.

Zoledronic acid administration failed to prevent bone loss at the knee in persons with acute spinal cord injury: an observational cohort study.

After acute spinal cord injury (SCI), rapid depletion of the sublesional skeleton occurs, particularly at the distal femur and proximal tibia. Subsequently, fragility fractures of the knee may occur. We determined the efficacy of zoledronic acid to prevent sublesional bone mineral density (BMD) loss at 6 and 12 months after acute SCI. Thirteen subjects with acute motor-complete SCI were prospectively studied: 6 patients received zoledronic acid (5 mg) and 7 subjects did not receive the drug (controls). Zoledronic acid was administered intravenously within 16 weeks of acute injury. Areal BMD was performed by dual energy X-ray absorptiometry at baseline, 6, and 12 months after administration of drug. The treatment group demonstrated sparing of BMD at the total hip at month 6 (p < 0.0006) and at month 12 (p < 0.01). In contrast to the findings at the hip, the treatment group had a greater loss of BMD compared to the control group at the distal femur and proximal tibia at month 6 (-7.9% ± 3.4 vs.-2.7% ± 5.0, respectively, p = 0.054; and -10.5% ± 6.4 vs. -4.8% ± 6.8, respectively, p = NS) and at month 12 (-18.5% ± 3.9 vs. -8.4% ± 7.2, respectively, p = 0.01; and -20.4% ± 8.8 vs.-7.9% ± 12.3, respectively, p = 0.06). A single dose of zoledronic acid administered soon after acute SCI reduced the %BMD loss at the hip, but appeared to have no effect to prevent %BMD loss at the knee, the site where fracture risk is greatest in persons with SCI.

Orthostatic responses to anticholinesterase inhibition in spinal cord injury.

INTRODUCTION: Acetylcholine (Ach) is the pre-synaptic neurotransmitter of the sympathetic nervous system. Increased pre-synaptic Ach may augment post-synaptic release of norepinephrine, thereby increasing systemic blood pressure (BP). OBJECTIVES: The primary objective of this investigation was to determine the hemodynamic effect of pyridostigmine bromide (PYRIDO: 60 mg), an Ach inhibitor (AchI), compared to no-drug (NO-D) during head-up tilt (HUT) in individuals with spinal cord injury (SCI). Secondarily, we aimed to determine the effects of PYRIDO compared to NO-D on symptoms of orthostatic intolerance (OI) and adverse event reporting (AE). METHODS: Ten individuals with SCI (C4-C7) were studied on two occasions: visit (1) NO-D and visit (2) PYRIDO. On each visit subjects underwent a progressive HUT maneuver to 15°, 25°, 35° for 5 min at each angle and 45 min at 45°. Supine and orthostatic heart rate (HR), systolic and diastolic BP (SBP and DBP), as well as monitored and symptoms of OI and AE were monitored and recorded. RESULTS: Supine hemodynamics did not differ between the trials. The significant fall in SBP during the NO-D trial was diminished with PYRIDO, and five subjects had an increased DBP during HUT with PYRIDO compared to the NO-D trial. Individuals that responded to PYRIDO with an increase in orthostatic BP had significantly lower resting HR than non-responders (p < 0.01), which suggests increased levels of pre-synaptic Ach. Subjective symptoms of OI and AE reporting did not differ between the two trials. CONCLUSIONS: These preliminary data suggest that PYRIDO is safe and may be effective at ameliorating the orthostatic fall in BP in select individuals with SCI.

Lipoprotein heterogeneity in persons with Spinal Cord Injury: a model of prolonged sitting and restricted physical activity.

BACKGROUND: Persons with spinal cord injury (SCI) often have low levels of physical activity, which predispose to increased adiposity and decreased high density lipoprotein cholesterol (HDL-C) concentrations, and, generally, normal low density lipoprotein cholesterol (LDL-C) concentrations. In spite of the mixed lipoprotein profile, the SCI population has been reported to have an elevated risk of cardiovascular-related morbidity and mortality. Nuclear magnetic resonance spectroscopy may permit a more precise quantification of lipoprotein particle (P) species, enabling a more accurate inference of risk for cardiovascular disease (CVD) in the SCI population. METHODS: Fasting blood samples were obtained on 83 persons with chronic SCI and 62 able-bodied (AB) subjects. Fasting plasma insulin (FPI), triglycerides (TG), and P number and size of VLDL (very low density lipoprotein), LDL, and HDL subclasses were determined. AB and SCI subjects were stratified based on HDL-C (i.e., Low <40 and Normal ≥ 40 mg/dl): AB-Normal (n = 48), AB-Low (n = 14), SCI-Normal (n = 49), and SCI-Low (n = 34). Factorial analyses of variance were performed to identify group differences in lipoprotein measurements. Pearson correlations were performed between the number of P by lipoprotein subclass, size, FPI, and TG. RESULTS: The SCI-Normal group was not significantly different from the AB-Normal group for body composition, FPI, TG or LP-IR and had negligible differences in the lipoprotein P profile, except for fewer number and smaller size of HDL-P. The SCI-Low group had a similar lipoprotein profile to that of the AB-Low group, but with a lipid P composition associated with a heightened atherogenic risk and greater tendency toward insulin resistance by the Lipoprotein-Insulin Resistance (LP-IR) score. In the SCI-Low group, the decreased number and reduced size of lipoprotein P were more prevalent and may be associated with increased waist circumference (i.e., abdominal adiposity), relatively elevated TG values (compared to the other subgroups), and an underlying subclinical state of insulin resistance. CONCLUSIONS: Prolonged sitting and restricted physical activity in individuals with SCI had the most profound effect on the HDL-C and its lipoprotein P subclasses, but not on LDL-C, however its P subclasses were also unfavorably affected but not to the same degree. The quantification of lipoprotein P characteristics may be a potent tool for the determination of risk for CVD in persons with SCI.

The relationship between the postprandial lipemic response and lipid composition in persons with spinal cord injury.

OBJECTIVE: To determine the influence of lipid concentration, lipid particle size, and total abdominal fat (TAF) on postprandial lipemic response (PPLr) in persons with spinal cord injury (SCI). METHODS: Thirty-five persons with SCI (17 paraplegia, 18 tetraplegia) and 18 able-bodied (AB) individuals participated. Following a 10-hour fast, blood was drawn for lipids, apolipoprotein (apo) A1 and B concentrations, and low-density (LSP) and high-density (HSP) lipoprotein particle sizes. A high-fat milkshake was consumed (∼1.3 g fat/kg). Blood was drawn at 2, 4, and 6 hours to determine PPLr, (triglyceride (TG) area under the curve). TAF and visceral (VF) fat were measured by ultrasonography; total body fat (TBF) by dual-energy X-ray absorptiometry. Differences between the groups were determined by independent sample t-tests. Pearson correlation coefficients determined the relationship among PPLr and lipids, and TAF. RESULTS: There were no significant differences in fasting TG, low-density lipoprotein (LDL), apoB, TAF, or PPLr values between the groups. In SCI, PPLr significantly correlated with: apoB (r = 0.63, P < 0.01, LSP (r = 0.57, P < 0.01), and TAF (r = 0.36, P < 0.01). After controlling for age and duration of injury, PPLr significantly correlated with apoB (r = 0.66, P = 0.001), TBF (r = 0.45, P = 0.03), VF (r = 0.66, P = 0.02), and TAF (r = 0.56, P = 0.007). CONCLUSIONS: Although concentrations of LDL cholesterol and apoB were not different between SCI and AB groups, LSP, apoB, and TAF correlated with PPLr in persons with SCI. ApoB was associated with a greater PPLr in those with motor complete SCI, after controlling for age and duration of injury.

Testosterone replacement therapy improves QTaVI in hypogonadal men with spinal cord injury.

AIM: To determine the effect of a 12-month intent-to-treat testosterone (T) replacement therapy (TRT) trial on QTa interval variability (QTaVI) in hypogonadal (HG) men with spinal cord injury (SCI). METHOD: A prospective, controlled 12-month TRT trial was completed in 22 healthy, chronic, nonambulatory men with SCI. Based on serum T concentration, subjects were designated as HG (≤ 11.3 nmol/l) or eugonadal (EG ≥ 11.4 nmol/l). Digital 3-lead electrocardiograms were performed. Heart rate (RR), heart rate variability [including total power (TPRR), low frequency (LFRR) and high frequency (HFRR)], QTa, QTe, and RT intervals, QTC (Bazett formula), QTVN, and QTaVI were calculated and evaluated at baseline and at 12 months. Lipoprotein profiles (triglycerides, total cholesterol, low-density and high-density lipoproteins) were obtained at the respective time points. RESULTS: Based on serum T concentration, 13 subjects were designated as HG and 11 as EG. During the trial, there were no group differences for RR, QTa, QTe or RT intervals, QTC, TPRR, HFRR, or lipoproteins. The HG group was older (p < 0.05) and their LFRR was lower (p < 0.05) at baseline. At baseline, QTaVI was significantly greater in the HG group compared to the EG group [-0.17 (0.92) vs. -1.07 (0.90); p < 0.05]. After TRT, this group difference was no longer present [-0.44 (0.87) vs. -0.65 (0.85)] and the change in the HG group was significant (p < 0.05). CONCLUSION: Hypogonadism in men with SCI was associated with elevated QTaVI at baseline. After 12 months of physiological TRT, the QTaVI improved in association with raising T into the normal range. These findings occurred independently of the prolongation of the QT interval.

Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury.

OBJECTIVE: To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml). DESIGN: Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study. RESULTS: The subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P < 0.05), weeks 8 and 10 (188 ± 95 vs. 228 ± 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 ± 95 vs. 259 ± 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated. CONCLUSION: Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI.

Prediction of limb lean tissue mass from bioimpedance spectroscopy in persons with chronic spinal cord injury.

BACKGROUND: Bioimpedance spectroscopy (BIS) is a non-invasive, simple, and inexpensive modality that uses 256 frequencies to determine the extracellular volume impedance (ECVRe) and intracellular volume impedance (ICVRi) in the total body and regional compartments. As such, it may have utility as a surrogate measure to assess lean tissue mass (LTM). OBJECTIVE: To compare the relationship between LTM from dual-energy X-ray absorptiometry (DXA) and BIS impedance values in spinal cord injury (SCI) and able-bodied (AB) control subjects using a cross-sectional research design. METHODS: In 60 subjects (30 AB and 30 SCI), a total body DXA scan was used to obtain total body and leg LTM. BIS was performed to measure the impedance quotient of the ECVRe and ICVRi in the total body and limbs. RESULTS: BIS-derived ECVRe yielded a model for LTM in paraplegia, tetraplegia, and control for the right leg (RL) (R(2) = 0.75, standard errors of estimation (SEE) = 1.02 kg, P < 0.0001; R(2) = 0.65, SEE = 0.91 kg, P = 0.0006; and R(2) = 0.54, SEE = 1.31 kg, P < 0.0001, respectively) and left leg (LL) (R(2) = 0.76, SEE = 1.06 kg, P < 0.0001; R(2) = 0.64, SEE = 0.83 kg, P = 0.0006; and R(2) = 0.54, SEE = 1.34 kg, P < 0.0001, respectively). The ICVRi was similarly predictive of LTM in paraplegia, tetraplegia, and AB controls for the RL (R(2) = 0.85, SEE = 1.31 kg, P < 0.0001; R(2) = 0.52, SEE = 0.95 kg, P = 0.003; and R(2) = 0.398, SEE = 1.46 kg, P = 0.0003, respectively) and LL (R(2) = 0.62, SEE = 1.32 kg, P = 0.0003; R(2) = 0.57, SEE = 0.91 kg, P = 0.002; and R(2) = 0.42, SEE = 1.31 kg, P = 0.0001, respectively). CONCLUSION: Findings demonstrate that the BIS-derived impedance quotients for ECVRe and ICVRi may be used as surrogate markers to track changes in leg LTM in persons with SCI.