Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force.

In randomized clinical trials (RCTs) for Alzheimer's Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer's Disease and Other Tauopathies.

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.

Lipid disorders: justification of methods and goals of treatment.

Dyslipidemia is a major risk factor for coronary heart disease (CHD). While some uncertainty exists about the clinical significance of improving high-density lipoprotein cholesterol and triglyceride levels, large primary- and secondary-prevention studies aimed at lowering low-density lipoprotein cholesterol levels with statins have convincingly reduced CHD events and total mortality. Despite the strong clinical evidence and widely publicized treatment guidelines, many hyperlipidemic patients receive inadequate lipid-lowering treatment. This failure to achieve clinical treatment goals may be due to poor physician adherence to treatment guidelines, patient noncompliance, and the presence of concomitant medical conditions that modify typical hyperlipidemia management. This review considers the challenges and available strategies to optimize lipid management in patients at risk for CHD.

ABCs of cardiovascular disease risk management.

The past 20 years have witnessed a marked decline in morbidity and mortality from cardiovascular disease. This decline has been due in large part to advances in coronary risk factor modification and a better understanding of the atherosclerotic process. Compelling scientific and clinical trial evidence proves that comprehensive risk factor modification extends patient survival and reduces cardiovascular and cerebrovascular events. This article reviews the ABCs of optimal medical and lifestyle management in patients with documented atherosclerotic vascular disease as well as in those adults who are at increased risk for the development of cardiovascular disease, based on contemporary clinical trial evidence.

Meningiomas: the decision not to operate.

In a consecutive series of 100 patients diagnosed with meningiomas, we advised 12 patients not to have surgery, and followed them from 3.3 to 12.8 years (mean, 8.8 years). The two determinants of this decision were either absence of related neurologic symptoms or signs and concern about high operative risk of neurologic impairment. Serial imaging studies showed meningioma growth in only one of the 12 unoperated patients and only one had convincing progression of neurologic impairment.

Hepatobiliary excretion of bile acids and rose bengal in streptozotocin-induced and genetic diabetic rats.

Divergent opinions regarding the effect of streptozotocin- (STZ) induced diabetes on bile flow rate may be due to the differing lengths of time after STZ administration at which bile flow was measured. Also, the biliary excretion of bile acids can influence the canalicular transport of several organic anions. Therefore, the hepatic clearance of the bile acid-dependent organic anion rose bengal was studied over a 30-day period in STZ-induced insulin-dependent Sprague-Dawley diabetic rats with elevated bile acid pools and in fatty noninsulin-dependent diabetic and lean Wistar rats. Excretion of total bile acids and rose bengal was higher in diabetic rats than in Sprague-Dawley control or lean or fatty Wistar rats. Depletion of bile acids for 10 hr in the 30-day STZ rat prevented the increased excretion of rose bengal. Bile flow rates in fatty and lean Wistar rats were similar to that in Sprague-Dawley controls. Increased bile acid excretion 7 and 14 days after STZ was not accompanied by the expected significant increase in bile flow, reflecting decreased bile acid-independent bile flow, regardless of method of calculation of bile flow (per g liver or per kg body weight). By 30 days, there were significant increases in bile acid excretion and bile flow. The increased clearance of rose bengal 7 days after STZ indicates that pathophysiological changes in the hepatocyte begin soon after the initiation of diabetes. Studies of taurocholate uptake into liver plasma membrane vesicles indicated that the maximal velocity of transport across the basolateral membrane was increased with no change in Km. This change was not observed in vesicles from insulin-treated diabetic rats. Therefore, studies employing STZ need to allow time for STZ toxicity to be overcome and for the pathology of diabetes to become established, to accurately reflect the diabetic condition.

Assessment of ventricular relaxation in the developing chick embryo using a monoexponential model.

In this study, the ventricular pressure decline during isovolumic relaxation in early diastole was modeled by regressing pressure and pressure change vs. time to a monoexponential formula: P(t) = P infinity+P0e-t/tau, where P(t) is ventricular pressure at time t, P infinity is the pressure in the fully relaxed ventricle, P0 is the pressure at the end of ventricular ejection, and tau is the ventricular relaxation rate constant. Analysis was performed on 330 ventricular pressure waveforms from 22 chick embryos, stages 17, 23, and 26, during baseline and following cardiac cycle length perturbation. Three computational models were evaluated. Based on analysis of the confidence intervals of estimates of P infinity and analysis of residuals, a least-squares nonlinear regression of pressure vs. time, which allowed estimates of tau and P infinity, best approximated the pressure decline. Isovolumic pressure decline in the embryonic heart is well approximated by a monoexponential model if both P infinity and tau are estimated. Negative values of P infinity during early stages of cardiac morphogenesis support the idea that diastolic suction plays a role in ventricular filling in the developing heart.

Sputum eosinophils from asthmatics express ICAM-1 and HLA-DR.

Sputum from symptomatic asthmatics is a rich source of eosinophils from the respiratory tract. Following liquefaction of sputum with dithioerythritol (DTE), a cell suspension for indirect double immunofluorescence with flow cytometry was obtained. Eosinophils were identified using anti-CD9 fluorescein conjugate, and particular surface markers measured with the relevant mouse MoAb followed by goat anti-mouse immunoglobulin phycoerythrin conjugate. Blood and sputum eosinophil surface markers were determined in parallel from asthmatics not receiving steroid therapy. Sputum eosinophils were found to have considerably elevated levels of CD11b, a reflection of eosinophil activation. Sputum but not blood eosinophils were found to express ICAM-1 (nine out of 11 cases) and HLA-DR (eight out of 11 cases). Furthermore, following culture of normal blood eosinophils with pooled T cell supernatants, ICAM-1 and HLA-DR could be induced in vitro. The induction of eosinophil adhesion molecules such as ICAM-1 and HLA-DR may influence eosinophil localization and function in asthma.