PIB is a non-specific imaging marker of amyloid-beta (Aβ) peptide-related cerebral amyloidosis

The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4′-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-ε4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Aβ) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Aβ-peptide related cerebral amyloidosi

Exercise Overrides Blunted Hypoxic Ventilatory Response in Prematurely Born Men.

Pre-term birth provokes life-long anatomical and functional respiratory system sequelae. Although blunted hypoxic ventilatory response (HVR) is consistently observed in pre-term infants, it remains unclear if it persists with aging and, moreover, if it influences hypoxic exercise capacity. In addition, it remains unresolved whether the previously observed prematurity-related alterations in redox balance could contribute to HVR modulation. Twenty-one prematurely born adult males (gestational age = 29 ± 4 weeks], and 14 age matched controls born at full term (gestational age = 39 ± 2 weeks) underwent three tests in a randomized manner: (1) hypoxia chemo-sensitivity test to determine the resting and exercise poikilocapnic HVR and a graded exercise test to volitional exhaustion in (2) normoxia (F <sub>i</sub> O <sub>2</sub> = 0.21), and (3) normobaric hypoxia (F <sub>i</sub> O <sub>2</sub> = 0.13) to compare the hypoxia-related effects on maximal aerobic power (MAP). Selected prooxidant and antioxidant markers were analyzed from venous samples obtained before and after the HVR tests. Resting HVR was lower in the pre-term (0.21 ± 0.21 L ⋅ min <sup>-1</sup> ⋅ kg <sup>-1</sup> ) compared to full-term born individuals (0.47 ± 0.23 L ⋅ min <sup>-1</sup> ⋅ kg <sup>-1</sup> ; p < 0.05). No differences were noted in the exercise HVR or in any of the measured oxidative stress markers before or after the HVR test. Hypoxia-related reduction of MAP was comparable between the groups. These findings indicate that blunted resting HVR in prematurely born men persists into adulthood. Also, active adults born prematurely seem to tolerate hypoxic exercise well and should, hence, not be discouraged to engage in physical activities in hypoxic environments. Nevertheless, the blunted resting HVR and greater desaturation observed in the pre-term born individuals warrant caution especially during prolonged hypoxic exposures

Personality Traits in Miners with Past Occupational Elemental Mercury Exposure

In this study, we evaluated the impact of long-term occupational exposure to elemental mercury vapor (Hg(0)) on the personality traits of ex-mercury miners. Study groups included 53 ex-miners previously exposed to Hg(0) and 53 age-matched controls. Miners and controls completed the self-reporting Eysenck Personality Questionnaire and the Emotional States Questionnaire. The relationship between the indices of past occupational exposure and the observed personality traits was evaluated using Pearson’s correlation coefficient and on a subgroup level by machine learning methods (regression trees). The ex-mercury miners were intermittently exposed to Hg(0) for a period of 7–31 years. The means of exposure-cycle urine mercury (U-Hg) concentrations ranged from 20 to 120 μg/L. The results obtained indicate that ex-miners tend to be more introverted and sincere, more depressive, more rigid in expressing their emotions and are likely to have more negative self-concepts than controls, but no correlations were found with the indices of past occupational exposure. Despite certain limitations, results obtained by the regression tree suggest that higher alcohol consumption per se and long-term intermittent, moderate exposure to Hg(0) (exposure cycle mean U-Hg concentrations > 38.7 < 53.5 μg/L) in interaction with alcohol remain a plausible explanation for the depression associated with negative self-concept found in subgroups of ex-mercury miners. This could be one of the reason for the higher risk of suicide among miners of the Idrija Mercury Mine in the last 45 years

Factors affecting the measurement variability of SV95C in ambulant patients with Duchenne muscular dystrophy

peer reviewedStride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD, and is an important real-world functional endpoint complementary to the traditional in-clinic assessments such as the North Star Ambulatory Assessment scale and the Six Meter Walk Test. The Context of Use of SV95C as defined by EMA states that SV95C should be measured for at least 50h during normal daily living to yield an outcome variability that would render SV95C suitable for regulatory decision-making. Considering the increasing use of SV95C in drug development for DMD, it is critical to understand the most common drivers of endpoint variability. Using data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD designed to longitudinally characterise functional disease progression using multiple outcome measures, we evaluated the impact of the time of day, the day of the week as well as seasonal changes on the measurement variability of SV95C in ambulant patients with DMD. Specifically, SV95C will be computed for morning only (8am-12pm) and afternoon recording periods (2pm-6pm) and compared. A similar sensitivity analysis will be done for SV95C computed on weekdays (Monday-Friday) and weekend (Saturday-Sunday). The seasonal impact on the compliance and SV95C will be conducted on longitudinal data and adjusted by the geographical location of the patients, restricting to countries where the maximal temperature difference over the year exceeds 15° and maximal temperature does not exceed 30°C. This data provides important context to the factors that impact the measurement variability of SV95C and will be useful to inform clinical trial design in DMD, when using SV95C as an outcome measure of efficacy

Longitudinal multi-centric study to assess the digital outcomes issued from wearable magneto-inertial devices in ambulant DMD

peer reviewedDuchenne muscular dystrophy is a muscle disease characterized by severe and rapidly progressive muscle weakness. One of the key challenges in treating this condition is identifying objective, reliable, and sensitive outcome measures to measure the effects of drug. For this purpose, the ActiMyo® (Sysnav, France), a magneto-inertial wearable device, was developed. Among the assessments with performed by this wearable device, the 95th centile stride velocity (SV95C) was qualified as the 2nd endpoint in 2019 by the European Medical Agency, representing the most rapid 5% of strides during real-life activities. The ActiLiège study is a multicentre clinical study with the aim of gathering data issued from a magneto-inertial wearable. Ambulant patients with DMD and healthy controls were included and will be followed up for three years. The patients wore the ActiMyo® on their ankle and wrist during the first 3 months after the inclusion and afterwards for one month every 3 months. Controls wear the device for a period of one month every 12 months. Digital outputs from the wearable sensors are compared to gold standard assessments. We enrolled seventy-six ambulant DMD patients aged between 4 and 20 years in 7 centres (Belgium, Poland, Hungary, Romania, Czech Republic, Slovenia, and Egypt). Thirty-five of them completed at least 1 year of follow-up. All ambulant patients were either on a 6-month stable course of steroids or started steroids at baseline. The baseline data of the patients and controls will be presented, along with longitudinal data that may provide an indication of sensitivity to change in comparison with other commonly performed outcomes

Analysis of the natural evolution of SV95C in ambulant patients with Duchenne muscular dystrophy

peer reviewedThe progressive nature of functional loss in Duchenne Muscular Dystrophy (DMD) is well established and routinely characterised in clinic using assessments such as the North Star Ambulatory Assessment and the Six Meter Walk Test. The trajectory of functional loss depends on the patient's age and baseline functional ability. There is a need to better characterise the trajectory of disease progression in order to try to predict disease evolution and optimise patient care. Stride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD and is an important real-world functional endpoint complementing the traditional in-clinic assessments. SV95C declines by approximately 7% per year in ambulant patients with DMD who are on a stable dose of steroids. In other functional endpoints such as the NSAA and 6MWT the decline is dependent on the patient's age and baseline ambulatory abilities. This study aims to investigate how yearly change of SV95C is also dependent upon age and baseline function. We will analyse how the evolution of SV95C can be predicted by the baseline value of SV95C and age, using non-linear and linear multiparametric regression models. This analysis will be conducted on data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD. This study was designed to characterise longitudinal functional disease progression using multiple outcome measures, including SV95C. It includes patients with DMD between 4 and 20 years old studied over 1 year. SV95C was measured daily using ActiMyo®, a class I CE medical device with two sensors worn on the ankles. These data will advance our understanding of the importance of SV95C as an outcome measure for functional disease progression in DMD