Abstract Background In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aβ) levels consistent with the presence of Alzheimer’s disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs. Methods Healthy elderly subjects ( n = 200; age 65–70 ( N = 100) and age > 70 ( N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aβ1-42 concentrations, plasma Aβ1-40, Aβ1-42, neurofilament light, and total Tau concentrations were measured. Aβ1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier. Results Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65–86) years. Twenty-four (27.3%) were Aβ positive for AD (age 65–83). The results of the logistic regression classifier showed that predictive features for Aβ positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10). Conclusion This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aβ levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs. Trial registration ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).
Sequence alterations in the promoter region of the vascular endothelial growth factor (VEGF) gene have been implicated in increasing the risk of developing ALS. VEGF promoter haplotypes were determined in 373 patients with sporadic ALS and 615 matched healthy controls in The Netherlands. No significant association between the previously reported at-risk haplotypes and ALS was found. Pooling our results with the previously studied population still showed a significant association with the AAG haplotype.
This chapter explains the importance of measuring mitochondrial function in drug trials. It focuses on features of a novel Cellular Oxygen METabolism (COMET) measurement system: The first bedside monitor of cellular oxygen metabolism. It is apparent that mitochondrial assessments are needed for development of novel drugs designed to enhance and/or maintain mitochondrial function. The ideal method of measuring mitochondrial function would be inexpensive and noninvasive, yet able to show multiple parameters of mitochondrial function, such as both oxygen consumption and phosphorous metabolism. Mitochondrial oxygen tension is measured by means of protoporphyrin IX-triplet state lifetime technique (PpIX-TSLT), and it is used to assess mitochondrial function in human skin cells in vivo. After introduction of the PpIX-TSLT as a new method to measure mitochondrial oxygen tension in vivo, the development of a clinical monitor was started. By using near-infrared spectroscopy (NIRS) and PpIX-TSLT techniques, increased in vivo oxygen consumption was revealed.
Aim We assessed whether total sleep deprivation (TSD) in combination with pain tests yields a reliable method to assess altered pain thresholds, which subsequently may be used to investigate (novel) analgesics in healthy subjects. Methods This was a two‐part randomized crossover study in 24 healthy men and 24 women. Subjects were randomized 1:1 to first complete a day of nonsleep‐deprived nociceptive threshold testing, followed directly by a TSD night and morning of sleep‐deprived testing, or first complete the TSD night and morning sleep‐deprived testing, returning 7 days later for a day of nonsleep‐deprived testing. A validated pain test battery (heat, pressure, electrical burst and stair, cold pressor pain test and conditioned pain modulation [CPM] paradigm) and sleep questionnaires were performed. Results Subjects were significantly sleepier after TSD as measured using sleepiness questionnaires. Cold pressor pain tolerance (PTT, estimate of difference [ED] −10.8%, 95% CI −17.5 to −3.6%), CPM PTT (ED −0.69 mA, 95% CI −1.36 to −0.03 mA), pressure PTT (ED −11.2%, 95% CI −17.5% to −4.3%) and heat pain detection thresholds (ED ‐0.74 °C, 95% CI −1.34 to −0.14 °C) were significantly decreased after TSD compared to the baseline morning assessment in the combined analysis (men + women). Heat hyperalgesia was primarily driven by an effect of TSD in men, whereas cold and pressure hyperalgesia was primarily driven by the effects of TSD observed in women. Conclusions TSD induced sex‐dependent hyperalgesia on cold, heat and pressure pain, and CPM response. These results suggest that the TSD model may be suitable to evaluate (novel) analgesics in early‐phase drug studies.
