Alzheimer’s Disease (AD) tau pathology originates in the brainstem and subsequently spreads to the entorhinal cortex, hippocampus and finally to temporal, parietal and prefrontal association cortices in a relatively stereotyped progression. Current evidence attributes this orderly progression to trans-neuronal spread of misfolded tau protein along the projection pathways of affected neurons. The aggregation of tau is being increasingly recognized as a trustworthy biomarker preceding the appearance of Alzheimer’s disease (AD) symptoms. One major goals of disease modifying therapies has been to stop or slow down the tau aggregation process. In order to evaluate drug efficacy, it would be desirable to have an accurate model predictive of a patient’s future tau burden, against which the tau measurements from drug-receiving cohorts could be compared. Here we report the development of such a model, evaluated in a cohort of 88 subjects clinically diagnosed as Mild Cognitively Impaired (MCI = 60) or Alzheimer’s disease (AD = 28) and tracked over a period of 18 months. Our approach combined data-driven and model-based methodologies, with the goal of predicting changes in tau within suitably specified target regions. We show that traditional statistical methods, allied to a network diffusion model for tau propagation in the brain, provide a remarkable prediction of the magnitude of incremental tau deposited in particular cortical areas of the brain over this period (MCI: R2 = 0.65±0.16; AD: R2 = 0.71±0.11) from baseline data. Our work has the potential to greatly strengthen the repertoire of analysis tools used in AD clinical trials, opening the door to future interventional trials with far fewer sample sizes than currently required.
The authors regret that they erroneously left a key contributor of their recently published manuscript entitled 'Development of a novel antibody to Calcitonin Gene-Related Peptide for the treatment of osteoarthritis-related pain'. The studies described in this article were the result of many years of work, across a number of divisions in their company.The erroneously failed to include Dr Nisenbaum, who was instrumental in the design and enablement of Laser Doppler Imaging to demonstrate functionality of antibodies to CGRP in vivo during the early phases of this project.The correct list of authors should read (with the missing author's name underlined):
BackgroundThe safety and efficacy of galcanezumab, a monoclonal antibody directed against CGRP, were assessed in a phase 2 clinical trial NCT02192190 in patients with moderate to severe osteoarthritis (OA) knee pain. Patients were randomized to placebo, galcanezumab (5, 25, 120 and 300 mg subcutaneously every 4 weeks, at weeks 0 and 4) or celecoxib (200 mg once daily) for 16 weeks in a 2:1:1:1:1:1 ratio. The study was terminated after an interim analysis due to inadequate efficacy for OA pain.ObjectivesThis study assessed the correlation of baseline plasma CGRP concentrations with signs, symptoms and radiographic severity of OA, and response to galcanezumab and celecoxib treatments.MethodsPlasma samples were collected at baseline and weeks 4, 8, 12 and 16 after study drug treatment. CGRP concentrations were determined by a validated high sensitivity (HS) assay. Correlation of baseline CGRP levels to WOMAC scores, PGA and radiographic Kellgren-Lawrence (K-L) grades were assessed using Spearman's correlation and Wilcoxon test. Patients were stratified into high vs low groups by baseline CGRP concentrations and post-treatment changes from baseline WOMAC scores evaluated by mixed effect model repeated measures for each subset.ResultsAt the interim analysis, baseline plasma CGRP samples were available for 262 patients with 54 patients providing samples at study termination through the week 8 visit. The median CGRP concentration at baseline was 1.07 pg/ml, range <0.78 to 33.91, and 31% of patients were below the level of quantitation (BLQ, <0.78 pg/ml). Median baseline CGRP levels were 1.0 pg/ml for K-L grade 2 (N=178), and 1.2 pg/ml for K-L grade 3 (N=84) (p=0.06). Correlations of WOMAC or PGA scores with baseline CGRP levels were all r <0.01 (showed no significant correlations). In OA patients receiving galcanezumab 300mg SC at week 0 and week 4, those with high baseline CGRP levels demonstrated a 14mm improvement in WOMAC Pain response at week 12, (95% CI 0, 29mm). The pain response to galcanezumab 300mg did not reach the magnitude of celecoxib response and no effects were seen at 5–120mg doses. Celecoxib treatment had larger pain reduction among patients with high baseline CGRP compared to low baseline CGRP levels. Treatment with celecoxib did not alter plasma CGRP concentrations.ConclusionsAt baseline, CGRP levels in OA patients were not associated with WOMAC or PGA scores. There was a modest association to radiographic K-L grade. Subgroup analyses of patients with high (>median) CGRP levels at baseline suggested a potential response to galcanezumab for the highest dose, 300mg, but not lower doses. Celecoxib response was greater in those with higher CGRP levels. However, interpretation was limited by small samples sizes at the latter time points. Further studies may determine if enriching the OA population for higher CGRP levels at baseline, or if increased or longer dosing of galcanezumab would improve pain responses or if CGRP blockade is relevant in relieving OA knee pain.Disclosure of InterestT. Mcnearney Share...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.