Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders

Most research on fluid biomarkers for central nervous system (CNS) disorders has so far been performed using cerebrospinal fluid (CSF) as the biomarker source. CSF has the advantage of being closer to the brain than serum or plasma with a relative enrichment of CNS-specific proteins that are present at very low concentrations in the blood and thus difficult to reliably quantify using standard immunochemical technologies. Recent technical breakthroughs in the field of ultrasensitive assays have started to change this. Here, we review the most established ultrasensitive quantitative technologies that are currently available to general biomarker laboratories and discuss their use in research on biomarkers for CNS disorders

An Elasticity Approach to Equity Risk Evaluation

This study defines and derives a measure of risk for real estate investment decisions using the concept of elasticity. Specifically, the elasticity of the after-tax equity yield with respect to the before-tax net operating cash flow growth rate is derived from a discounted cash flow equity valuation model. Also, an illustration of the use and interpretation of this elasticity measure is provided.

The impact of a population-level school food and nutrition policy on dietary intake and body weights of Canadian children

AbstractObjectiveThe objective of this study is to assess population-level trends in children's dietary intake and weight status before and after the implementation of a provincial school nutrition policy in the province of Nova Scotia, Canada.MethodSelf-reported dietary behavior and nutrient intake and measured body mass index were collected as part of a population-level study with grade 5 students in 2003 (n=5215) and 2011 (5508), prior to and following implementation of the policy. We applied random effects regression methods to assess the effect of the policy on dietary and health outcomes.ResultsIn 2011, students reported consuming more milk products, while there was no difference in mean consumption of vegetables and fruits in adjusted models. Adjusted regression analysis revealed a statistically significant decrease in sugar-sweetened beverage consumption. Despite significant temporal decreases in dietary energy intake and increases in diet quality, prevalence rates of overweight and obesity continued to increase.ConclusionThis population-level intervention research suggests a positive influence of school nutrition policies on diet quality, energy intake and healthy beverage consumption, and that more action beyond schools is needed to curb the increases in the prevalence of childhood obesity

Comparison of ICD code-based diagnosis of obesity with measured obesity in children and the implications for health care cost estimates

<p>Abstract</p> <p>Background</p> <p>Administrative health databases are a valuable research tool to assess health care utilization at the population level. However, their use in obesity research limited due to the lack of data on body weight. A potential workaround is to use the ICD code of obesity to identify obese individuals. The objective of the current study was to investigate the sensitivity and specificity of an ICD code-based diagnosis of obesity from administrative health data relative to the gold standard measured BMI.</p> <p>Methods</p> <p>Linkage of a population-based survey with anthropometric measures in elementary school children in 2003 with longitudinal administrative health data (physician visits and hospital discharges 1992-2006) from the Canadian province of Nova Scotia. Measured obesity was defined based on the CDC cut-offs applied to the measured BMI. An ICD code-based diagnosis obesity was defined as one or more ICD-9 (278) or ICD-10 code (E66-E68) of obesity from a physician visit or a hospital stay. Sensitivity and specificity were calculated and health care cost estimates based on measured obesity and ICD-based obesity were compared.</p> <p>Results</p> <p>The sensitivity of an ICD code-based obesity diagnosis was 7.4% using ICD codes between 2002 and 2004. Those correctly identified had a higher BMI and had higher health care utilization and costs.</p> <p>Conclusions</p> <p>An ICD diagnosis of obesity in Canadian administrative health data grossly underestimates the true prevalence of childhood obesity and overestimates the health care cost differential between obese and non-obese children.</p

Characteristics of improvements in balance control using vibro-tactile biofeedback of trunk sway for multiple sclerosis patients

Background and aims: Previously, we determined that training with vibrotactile feedback (VTfb) of trunk sway improves MS patients’ balance impairment. Here, we posed 5 questions: 1) How many weeks of VTfb training are required to obtain the best short-term carry over effect (CoE) with VTfb? 2) How long does the CoE last once VTfb training terminates? 3) Is the benefit similar for stance and gait? 4) Is position or velocity based VTfb more effective in reducing trunk sway? 5) Do patients’ subjective assessments of balance control improve? Methods: Balance control of 16 MS patients was measured with gyroscopes at the lower trunk. The gyroscopes drove directionally active VTfb in a head-band. Patients trained twice per week with VTfb for 4 weeks to determine when balance control with and without VTfb stopped improving. Thereafter, weekly assessments without VTfb over 4 weeks and at 6 months determined when CoEs ended. Results: A 20% improvement in balance to normal levels occurred with VTfb. Short term CoEs improved from 15 to 20% (p ≤0.001). Medium term (1–4 weeks) CoEs were constant at 19% (p ≤0.001). At 6 months improvement was not significant, 9%. Most improvement was for lateral sway. Equal improvement occurred when angle position or velocity drove VTfb. Subjectively, balance improvements peaked after 3 weeks of training (32%, p ≤0.05). Conclusions: 3–4 weeks VTfb training yields clinically relevant sway reductions and subjective improvements for MS patients during stance and gait. The CoEs lasted at least 1 month. Velocity-based VTfb was equally effective as position-based VTf

Plasma neurofilament light chain: an early biomarker for hereditary ATTR amyloid polyneuropathy

BACKGROUND: Transthyretin amyloidosis due to V30M mutation (ATTR-V30M) is the most frequent hereditary ATTR amyloidosis. Besides neurophysiological measures, there are no biomarkers to detect preclinical disease or monitor disease progression. CSF or plasma neurofilament light chain (pNfL) have recently been considered sensitive biomarkers to quantitate neuro-axonal damage in several disorders of the peripheral and central nervous system. OBJECTIVE: Characterise plasma NfL levels in a series of untreated ATTR-V30M patients stratified by clinical severity using a cross-sectional retrospective study design. METHODS: Sixty ATTR-V30M patients and 16 controls from 2 independent cohorts were analysed for pNfL by single-molecule array assay (SIMOA) technique. Disease severity was assessed with Polyneuropathy Disability Score. RESULTS: pNfL is elevated in ATTR-V30M patients as a function of disease severity in both cohorts. Moreover, pNfL discriminates asymptomatic mutation carriers from early symptomatic patients (AUC = 0.97; p 66.9 pg/mL) also discriminates patients with sensory neuropathy from patients with motor neuropathy (AUC = 0.91; p < .01) with a sensitivity of 61.5% and a specificity of 92.3%. CONCLUSION: pNfL is an easily accessible biomarker to establish ATTR-V30M disease conversion and to monitor disease progression. pNfL could be used as efficacy measure of disease-oriented therapies in clinical and pre-clinical trials

Prognostic biomarkers in primary progressive multiple sclerosis: validating and scrutinizing multimodal evoked potentials

OBJECTIVE: To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. METHODS: Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0-6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. RESULTS: Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45-0.69; p < 0.01) and follow-up (Rho: 0.59-0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R(2)adj: 0.24), while EDSS and age did not. Tibial qSEP (R(2)adj: 0.22) and qMEP (R(2)adj: 0.26) were the best single modality predictors, outperformed by their combination (R(2)adj: 0.32). CONCLUSIONS: Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. SIGNIFICANCE: Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS

Neurofilament results for the phase II neuroprotection study of phenytoin in optic neuritis

Background: A randomized trial of phenytoin in acute optic neuritis (ON) demonstrated a 30% reduction in retinal nerve fiber layer (RNFL) loss with phenytoin versus placebo. Here we present the corresponding serum neurofilament analyses. Methods: Eighty-six acute ON cases were randomized to receive phenytoin (4–6 mg/kg/day) or placebo for 3 months, and followed up for 6 months. Serum was collected at baseline, 3 and 6 months for analysis of neurofilament heavy chain (NfH) and neurofilament light chain (NfL). Results: Sixty-four patients had blood sampling. Of these, 58 and 56 were available at 3 months, and 55 and 54 were available at 6 months for NfH and NfL, respectively. There was no significant correlation between serum NfH and NfL at the time points tested. For NfH, the difference in mean placebo – phenytoin was −44 pg/ml at 3 months (P = 0.019) and −27 pg/ml at 6 months (P = 0.234). For NfL, the difference was 1.4 pg/ml at 3 months (P = 0.726) and −1.6 pg/ml at 6 months (P = 0.766). Conclusions: At 3 months, there was a reduction in NfH, but not NFL, in the phenytoin versus placebo group, while differences at 6 months were not statistically significant. This suggests a potential neuroprotective role for phenytoin in acute ON, with the lower NfH at 3 months, when levels secondary to degeneration of the anterior visual pathway are still elevated, but not at 6 months, when levels have normalized

A case series on the value of tau and neurofilament protein levels to predict and detect delirium in cardiac surgery patients

BACKGROUND: Delirium following cardiac surgery is a relevant complication in the majority of elderly patients but its prediction is challenging. Cardiopulmonary bypass, essential for many interventions in cardiac surgery, is responsible for a severe inflammatory response leading to neuroinflammation and subsequent delirium. Neurofilament light protein (NfL) and tau protein (tau) are specific biomarkers to detect neuroaxonal injury as well as glial fibrillary acidic protein (GFAP), a marker of astrocytic activation. METHODS: We thought to examine the perioperative course of these markers in a case series of each three cardiac surgery patients under off-pump cardiac arterial bypass without evolving delirium (OPCAB-NDEL), patients with a procedure under cardio-pulmonary bypass (CPB) without delirium (CPB-NDEL) and delirium after a CPB procedure (CPB-DEL). Delirium was diagnosed by the Confusion Assessment Method for the ICU and chart reviews. RESULTS: We observed increased preoperative levels of tau in patients with later delirium, whereas values of NfL and GFAP did not differ. In the postoperative course, all biomarkers increased multi-fold. NfL levels sharply increased in patients with CPB reaching the highest levels in the CPB-DEL group. CONCLUSION: Tau and NfL might be of benefit to identify patients in cardiac surgery at risk for delirium and to detect patients with the postoperative emergence of delirium

Changes in serum neurofilament light chain levels following narrowband ultraviolet B phototherapy in clinically isolated syndrome

Objective To determine whether serum neurofilament light chain (sNfL) levels are suppressed in patients with the clinically isolated syndrome (CIS) following narrowband ultraviolet B phototherapy (UVB-PT). Methods sNfL levels were measured using a sensitive single-molecule array assay at baseline and up to 12 months in 17 patients with CIS, 10 of whom received UVB-PT, and were compared with healthy control (HC) and early relapsing remitting multiple sclerosis (RRMS) group. sNfL levels were correlated with magnetic resonance imaging total lesion volume (LV) determined using icobrain version 4.4.1 and with clinical outcomes. Results Baseline median sNfL levels were significantly higher in the CIS (20.6 pg/mL, interquartile range [IQR] 13.7–161.4) and RRMS groups (36.6 pg/ml [IQR] 16.2–212.2) than in HC (10.7 pg/ml [IQR] 4.9–21.5) (p = .012 and p = .0002, respectively), and were strongly correlated with T2 and T1 LV at 12 months (r = .800; p = .014 and r = .833; p = .008, respectively) in the CIS group. Analysis of changes in sNfL levels over time in the CIS group showed a significant cumulative suppressive effect of UVB-PT in the first 3 months (UVB-PT −10.6% vs non-UVB-PT +58.3%; p = .04) following which the levels in the two groups converged and continued to fall. Conclusions Our findings provide the basis for further studies to determine the utility of sNfL levels as a marker of neuro-axonal damage in CIS and early MS and for assessing the efficacy of new therapeutic interventions such as UVB-PT