Longitudinal Exposure-Response Modeling of Multiple Indicators of Alzheimer's Disease Progression.

BACKGROUND: Progression in Alzheimer's disease manifests as changes in multiple biomarker, cognitive, and functional endpoints. Disease progression modeling can be used to integrate these multiple measures into a synthesized metric of where a patient lies within the disease spectrum, allowing for a more dynamic measure over the range of the disease. OBJECTIVES: This study aimed to combine modeling techniques from psychometric research (e.g., item response theory) and pharmacometrics (e.g., hierarchical models) to describe the multivariate longitudinal disease progression for patients with mild-to-moderate Alzheimer's disease. Additionally, we aimed to extend the subsequent model to make it suitable for clinical trial simulation, with the inclusion of covariates, to explain variability in latent progression (i.e., disease progression) and to aid in the assessment of enrichment strategies. DESIGN: Multiple longitudinal endpoints in the Alzheimer's Disease Neuroimaging Initiative database were modeled. This model was validated internally using visual predictive checks, and externally by comparing data from the placebo arms of two Phase 2 crenezumab studies, ABBY (NCT01343966) and BLAZE (NCT01397578). SETTING: The Alzheimer's Disease Neuroimaging Initiative began in 2004: the initial 5-year study (ADNI-1) was extended by 2 years in 2009 by a Grand Opportunities grant (ADNI-GO), and in 2011 and 2016 by further competitive renewals of the ADNI-1 grant (ADNI-2 and ADNI-3, respectively). This work studies natural progression data from patients with confirmed Alzheimer's disease. The Phase 2 ABBY and BLAZE trials evaluated the safety and efficacy of crenezumab in patients with mild-to-moderate Alzheimer's disease. PARTICIPANTS: From the Alzheimer's Disease Neuroimaging Initiative database, 305 subjects who had a baseline diagnosis of mild-to-moderate Alzheimer's disease were included in modeling. From the ABBY and BLAZE studies, 158 patients were included from the studies' placebo arms. MEASUREMENTS: Longitudinal cognitive and functional assessments modeled included the Clinical Dementia Rating (both as Sum of Boxes and individual item scores), the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scale - Cognitive Subscale, the Functional Activities Questionnaire, the Montreal Cognitive Assessment, and the Rey Auditory Verbal Learning Test. Also included were the imaging variable fluorodeoxyglucose-positron emission tomography and the following magnetic resonance imaging volumetrics: entorhinal, fusiform, hippocampal, intra-cranial, mid-temporal, ventricular, and whole brain. RESULTS: Applying item response theory approaches in this longitudinal setting showed clinical assessments informing a common disease scale in the following order (from early disease to late disease): Rey Auditory Verbal Learning Test, Functional Activities Questionnaire, Montreal Cognitive Assessment, Alzheimer's Disease Assessment Scale - Cognitive Subscale 12, Clinical Dementia Rating - Sum of Boxes, and Mini-Mental State Examination. The Clinical Dementia Rating communication and home-and-hobbies items were most informative at earlier disease stages, while memory, orientation, and personal care informed the disease status at later stages. A clinical trial simulation model was developed and accurately described within-sample longitudinal distribution of endpoints. Simplifying the model to use only baseline age, MMSE, and APOEε4 status as predictors, out-of-sample mean progression of ADAS-Cog and CDR Sum of Boxes in the ABBY and BLAZE placebo arms was accurately described; however, the variability in these endpoints was underpredicted and suggests possibility for further model refinement when extrapolating from the ADNI sample to trial data. Clinical trial simulations were performed to exemplify use of the model to investigate hypothetical disease modification effects on the multivariate, longitudinal progression on the Alzheimer's Disease Assessment Scale - Cognitive Subscale and the Clinical Dementia Rating - Sum of Boxes. CONCLUSIONS: The latent variable structure of item response theory can be extended to capture a variety of scales that are common assessments and indicators of disease status in mild-to-moderate Alzheimer's disease. These models are not intended to support causal inferences, but they do successfully characterize the observed correlation between endpoints over time and result in concise numerical indices of disease status that reflect the totality of evidence from considering the endpoints jointly. As such, the models have utility for a variety of tasks in clinical trial design, including simulation of hypothetical drug effects, interpolation of missing data, and assessment of in-sample information.

Neurofilament light as a predictive biomarker of unresolved chemotherapy-induced peripheral neuropathy in subjects receiving paclitaxel and carboplatin.

Management of chemotherapy-induced peripheral neuropathy (CIPN) remains a significant challenge in the treatment of cancer. Risk mitigation for CIPN involves preemptive reduction of cumulative dose or reduction of dose intensity upon emergence of symptoms, despite the risk of reduced tumor efficacy. A predictive biomarker for dose-limiting CIPN could improve treatment outcomes by allowing providers to make informed decisions that balance both safety and efficacy. To identify a predictive biomarker of CIPN, markers of neurodegeneration neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), tau and ubiquitin c-terminal hydrolase L1 (UCHL1) were assessed in serum of up to 88 subjects drawn 21 days following the first of 6 treatments with chemotherapeutics paclitaxel and carboplatin. Serum NfL and GFAP were increased with chemotherapy. Further, NfL change predicted subsequent onset of grade 2-3 CIPN during the remainder of the trial (mean treatment duration = 200 days) and trended toward stronger prediction of CIPN that remained unresolved at the end of the study. These results confirm previous reports that serum NfL is increased in CIPN and provide the first evidence that NfL can be used to identify subjects susceptible to dose-limiting paclitaxel and carboplatin induced CIPN prior to onset of symptoms.

Bruton's tyrosine kinase is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.

Bcr-Abl, a constitutively active tyrosine kinase, is the cause of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias (ALL). Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases with a crucial role in B-cell development, is consistently tyrosine phosphorylated in Bcr-Abl expressing murine pre B cells. BTK has been implicated in Bcr-Abl-mediated B-cell transformation and resistance to imatinib, implying that inhibiting BTK may be therapeutically beneficial. We decided to test whether BTK is a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells. We depleted BTK in Ba/F3 and 32D cells expressing native and kinase domain (KD) mutant (E255K and T315I) Bcr-Abl, using shRNA. BTK levels were reduced to <10% of controls. However, no differences in viability and cell proliferation were observed and the response to imatinib was not altered. Consistent with this, proliferation and viability were unaffected by inhibition of BTK with reversible (PC-005) and irreversible (PCI-31523) small molecule inhibitors. Lastly, BTK inhibition did not affect the ability of Bcr-Abl to transform primary murine hematopoietic cells in colony forming and B-cell transformation assays. Collectively this data argues against a critical role for BTK in Bcr-Abl-mediated leukemogenesis.

Establishment of left/right asymmetry in neuroblast migration by UNC-40/DCC, UNC-73/Trio and DPY-19 proteins in C. elegans.

The bilateral C. elegans neuroblasts QL and QR are born in the same anterior/posterior (A/P) position, but polarize and migrate left/right asymmetrically: QL migrates toward the posterior and QR migrates toward the anterior. After their migrations, QL but not QR switches on the Hox gene mab-5. We find that the UNC-40/netrin receptor and a novel transmembrane protein DPY-19 are required to orient these cells correctly. In unc-40 or dpy-19 mutants, the Q cells polarize randomly; in fact, an individual Q cell polarizes in multiple directions over time. In addition, either cell can express MAB-5. Both UNC-40 and DPY-19, as well as the Trio/GTPase exchange factor homolog UNC-73, are required for full polarization and migration. Thus, these proteins appear to participate in a signaling system that orients and polarizes these migrating cells in a left/right asymmetrical fashion during development. The C. elegans netrin UNC-6, which guides many cells and axons along the dorsoventral axis, is not involved in Q cell polarization, suggesting that a different netrin-like ligand serves to polarize these cells along the anteroposterior axis.

Neuronal cell migration in C. elegans: regulation of Hox gene expression and cell position.

In C. elegans, the Hox gene mab-5, which specifies the fates of cells in the posterior body region, has been shown to direct the migrations of certain cells within its domain of function. mab-5 expression switches on in the neuroblast QL as it migrates into the posterior body region. mab-5 activity is then required for the descendants of QL to migrate to posterior rather than anterior positions. What information activates Hox gene expression during this cell migration? How are these cells subsequently guided to their final positions? We address these questions by describing four genes, egl-20, mig-14, mig-1 and lin-17, that are required to activate expression of mab-5 during migration of the QL neuroblast. We find that two of these genes, egl-20 and mig-14, also act in a mab-5-independent way to determine the final stopping points of the migrating Q descendants. The Q descendants do not migrate toward any obvious physical targets in wild-type or mutant animals. Therefore, these genes appear to be part of a system that positions the migrating Q descendants along the anteroposterior axis.