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BACKGROUND Monoclonal antibodies that target amyloid-beta CAB) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully hunlan, anti-Aβ IgGl monocional antibody with highest affinity for aggregated AB that has been tested for the treatment of Alzheimer's disease. METHODS We conducted two phase 3 trials (GRADUATE I and ID involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alz- heimer' s disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS A total of985 and 980 participants were enrolled in the GRADUATE I and H trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval ICI], -0.66 to 0.05; P=O.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95° CI, -0.55 to 0.17; P=O.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the tWO trialS. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of A/342 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS Among persons with early Alzheimer's disease, the use of gantenerumab led to lower amyloid plague burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.) [ABSTRACT FROM AUTHOR]

Background: The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.Methods: We conducted an 18-month, multicenter, double-blind, phase 3 trial involving persons 50 to 90 years of age with early Alzheimer's disease (mild cognitive impairment or mild dementia due to Alzheimer's disease) with evidence of amyloid on positron-emission tomography (PET) or by cerebrospinal fluid testing. Participants were randomly assigned in a 1:1 ratio to receive intravenous lecanemab (10 mg per kilogram of body weight every 2 weeks) or placebo. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). Key secondary end points were the change in amyloid burden on PET, the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90; higher scores indicate greater impairment), the Alzheimer's Disease Composite Score (ADCOMS; range, 0 to 1.97; higher scores indicate greater impairment), and the score on the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL; range, 0 to 53; lower scores indicate greater impairment).Results: A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). In a substudy involving 698 participants, there were greater reductions in brain amyloid burden with lecanemab than with placebo (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Other mean differences between the two groups in the change from baseline favoring lecanemab were as follows: for the ADAS-cog14 score, -1.44 (95% CI, -2.27 to -0.61; P<0.001); for the ADCOMS, -0.050 (95% CI, -0.074 to -0.027; P<0.001); and for the ADCS-MCI-ADL score, 2.0 (95% CI, 1.2 to 2.8; P<0.001). Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities with edema or effusions in 12.6%.Conclusions: Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer's disease. (Funded by Eisai and Biogen; Clarity AD ClinicalTrials.gov number, NCT03887455.). [ABSTRACT FROM AUTHOR]

Background: Brain amyloid-beta (Aβ) plaques, a hallmark of the pathophysiology of Alzheimer's disease, have been associated with frailty. Whether the plasma Aβ markers show similar relationship with frailty is unknown., Objectives: To investigate the prospective associations between plasma Aβ42/40 ratio and overtime frailty in community-dwelling older adults., Methods: From the 5-year Multidomain Alzheimer Preventive Trial (MAPT), we included 477 adults ≥70 years with available data on plasma Aβ42/40 ratio (lower is worse). Fried frailty phenotype (robust, pre-frail and frail) was assessed at the same time-point of plasma Aβ measures and after until the end of follow-up. The outcomes of interest were the change in the frailty phenotype over time (examined by mixed-effect ordinal logistic regressions) and incident frailty (examined by Cox proportional hazard models)., Results: Plasma Aβ42/40 did not show significant associations with incident frailty; however, after adjusting for Apolipoprotein E (APOE) ε4 genotype, people in the lower quartile of plasma Aβ42/40 (≤0.103) had higher risk of incident frailty (HR=2.63; 95% CI, 1.00 to 6.89), compared to those in the upper quartile (>0.123). Exploratory analysis found a significant association between the lower quartile of plasma Aβ42/40 and incident frailty among APOE ε4 non-carriers (HR=3.48; 95% CI, 1.19 to 10.16), but not among carriers. No associations between plasma Aβ42/40 and evolution of frailty were observed., Conclusion: No significant associations between plasma Aβ42/40 and frailty were found when APOE ε4 status was not accounted into the model. Nevertheless, APOE ε4 non-carriers with high Aβ burden might be more susceptible to develop frailty., Competing Interests: Washington University and Randall Bateman have equity ownership interest in C2N Diagnostics and receive income based on technology (blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Plasma Based Methods for Determining A-Beta Amyloidosis.” RJB has received honoraria as a speaker/consultant/advisory board member from Amgen, AC Immune, Eisai, Hoffman-LaRoche, and Janssen; and reimbursement of travel expenses from AC Immune, Hoffman-La Roche and Janssen.

There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential., Competing Interests: The Task Force was partially funded by registration fees from industrial participants. These corporations placed no restrictions on this work. Dr. Bateman reports grants from BrightFocus Foundation, Pharma Consortium (Abbvie, AstraZeneca, Biogen, Eisai, Eli Lilly and Co., Hoffman La-Roche Inc., Janssen, Pfizer, Sanofi-Aventi), the Tau SILK/PET Consortium (Biogen/Abbvie/Lilly), Association for Frontotemporal Degeneration FTD Biomarkers Initiative, Anonymous Foundation, GHR Foundation, NIH, Alzheimer’s Association, Lilly, Rainwater Foundation Tau Consortium, and Cure Alzheimer’s Fund, grants, personal fees and non-financial support from Roche and Janssen, personal fees and non-financial support from Pfizer, Eisai, and Merck, and non-financial support from Avid Radiopharmaceuticals outside the submitted work. Washington University, Dr. Bateman, and David Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. Rachelle Doody is full time employee of Genetic/Roche. Dr Schindler travels fees received as member of CTAD organizing committee. Dr. Weiner reports grants and other from NIH, grants from DOD, grants from Johnson and Johnson, grants from Kevin and Connie Shanahan, grants from General Electric, grants from PCORI, grants from CA Dept of Public Health, grants from Veterans Administration, grants from U. of M, grants from Australian Catholic U., grants from Biogen, grants from Hillblom Foundation, grants and other from Alzheimer’s Association, grants from Stroke Foundation, grants from Siemens, other from Bioclinica, other from Accera, Inc./Cerecin, other from Genentech, other from Indiana U., other from CHU Toulouse, other from St. George Hospital U, other from Eli Lilly, other from Roche, other from Lynch Group, LLC, other from Dolby Family Ventures, other from Nestec, other from Health and Wellness Partners, other from AC Immune, other from Alzheon, Inc., other from Japanese Government Alliance, other from ATRI/ACTC, other from U. of Melbourne, other from U. Tokyo, other from National Cntr for Geriatrics and Gerontology (Japan), outside the submitted work. Dr. Aisen reports grants from Lilly, personal fees from Proclara, other from Lilly, other from Janssen, other from Eisai, grants from Janssen, grants from NIA, grants from FNIH, grants from Alzheimer’s Association, personal fees from Merck, personal fees from Roche, personal fees from Lundbeck, personal fees from Biogen, personal fees from ImmunoBrain Checkpoint, outside the submitted work. Dr. Vellas reports grants from Lilly, Merck, Roche, Lundbeck, Biogen, grants from Alzheimer’s Association, European Commission, personal fees from Lilly, Merck, Roche, Biogen, outside the submitted work.

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., Competing Interests: TW, IHH, PBV, and IF are full time employees and/or advisors of C2N Diagnostics, receiving stock and/or stock options. RJB is a co-founder of C2N Diagnostics. RJB and Washington University in St. Louis have equity ownership interest in C2N Diagnostics and may receive royalty income based on technology licensed by Washington University to C2N Diagnostics. RJB receives lab research funding from the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.), Eli Lilly and Co, Hoffman La-Roche, Janssen, Avid Radiopharmaceuticals, and the DIAN Pharma Consortium (Abbvie, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly and Co, Hoffman La-Roche, Janssen, Pfizer, and Sanofi). RJB has received honoraria from Janssen and Pfizer as a speaker and from Merck and Pfizer as an Advisory Board member. In addition, RJB receives income from C2N Diagnostics for serving on the Scientific Advisory Board. JBB is a co-founder and employee of C2N Diagnostics, receiving stock and/or stock options. KB, HF, and NM are employees of AbbVie, receiving stock and/or stock options. DMH co-founded and is on the scientific advisory board of C2N Diagnostics. DMH is an inventor on a submitted patent “Antibodies to Tau”, PCT/US2013/049333, that is licensed by Washington University to C2N Diagnostics. This patent was subsequently licensed to AbbVie. DMH receives research grants from the C2N Diagnostics, AbbVie, Eli Lilly, and Denali. DMH consults for Genentech, AbbVie, Eli Lilly, Proclara Biosciences, Glaxosmithkline, and Denali.

The Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) was formed to direct the design and management of interventional therapeutic trials of international DIAN and autosomal dominant Alzheimer's disease (ADAD) participants. The goal of the DIAN-TU is to implement safe trials that have the highest likelihood of success while advancing scientific understanding of these diseases and clinical effects of proposed therapies. The DIAN-TU has launched a trial design that leverages the existing infrastructure of the ongoing DIAN observational study, takes advantage of a variety of drug targets, incorporates the latest results of biomarker and cognitive data collected during the observational study, and implements biomarkers measuring Alzheimer's disease (AD) biological processes to improve the efficiency of trial design. The DIAN-TU trial design is unique due to the sophisticated design of multiple drugs, multiple pharmaceutical partners, academics servings as sponsor, geographic distribution of a rare population and intensive safety and biomarker assessments. The implementation of the operational aspects such as home health research delivery, safety magnetic resonance imagings (MRIs) at remote locations, monitoring clinical and cognitive measures, and regulatory management involving multiple pharmaceutical sponsors of the complex DIAN-TU trial are described., (Published by Elsevier Masson SAS.)

β-adrenergic receptors are a class of G protein-coupled receptors that have essential roles in regulating heart rate, blood pressure, and other cardiorespiratory functions. Although the role of β adrenergic receptors in the peripheral nervous system is well characterized, very little is known about their role in the central nervous system despite being localized in many brain regions involved in autonomic activity and regulation. Since parasympathetic activity to the heart is dominated by cardiac vagal neurons (CVNs) originating in the nucleus ambiguus (NA), β adrenergic receptors localized in the NA represent a potential target for modulating cardiac vagal activity and heart rate. This study tests the hypothesis that activation of β adrenergic receptors alters the membrane properties and synaptic neurotransmission to CVNs. CVNs were identified in brainstem slices, and membrane properties and synaptic events were recorded using the whole-cell voltage-clamp technique. The nonselective β agonist isoproterenol significantly decreased inhibitory GABAergic and glycinergic as well as excitatory glutamatergic neurotransmission to CVNs. In addition, the β(1)-selective receptor agonist dobutamine, but not β(2) or β(3) receptor agonists, significantly decreased inhibitory GABAergic and glycinergic and excitatory glutamatergic neurotransmission to CVNs. These decreases in neurotransmission to CVNs persisted in the presence of tetrodotoxin (TTX). These results provide a mechanism by which activation of adrenergic receptors in the brainstem can alter parasympathetic activity to the heart. Likely physiological roles for this adrenergic receptor activation are coordination of parasympathetic-sympathetic activity and β receptor-mediated increases in heart rate upon arousal., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

The cholinergic cardiac vagal neurons (CVNs), located in the nucleus ambiguus, are the origin of cardioinhibitory parasympathetic activity. Catecholaminergic neurons in nearby regions of the brainstem, including the C1 and C2 cell groups, are thought to play a key role in both arousing from sleep and maintaining wakefulness. Because norepinephrine (NE) could play an important role in influencing the activity of CVNs, particularly in response to sleeping/waking and arousal states, the present study investigated the contribution of α(1)-adrenergic receptor activation to augment inhibitory and/or blunt excitatory neurotransmission to CVNs. To test the effects of α(1)-adrenergic receptor activation, CVNs were labeled in rats by retrograde tracing and synaptic events were recorded by whole cell voltage clamp techniques in vitro. Prazosin, an inverse agonist of α(1)-adrenergic receptor, significantly decreased the frequency of both GABAergic and glycinergic neurotransmission to CVNs. Activation of α(1)-adrenergic receptors by the α(1)-adrenergic receptor agonists NE or phenylephrine (PE) both significantly increased GABAergic and glycinergic inhibitory event frequency. This effect was prevented by the sodium channel blocker tetrodotoxin (TTX). Activation of α(1)-adrenergic receptors did not alter glutamatergic neurotransmission to CVNs. This study indicates that α(1)-adrenergic receptor activation in the brainstem can facilitate inhibitory GABAergic and glycinergic neurotransmission so as to reduce CVN activity; this synaptic modulation may play a role in the tachycardia seen during NE-dependent behavioral arousal., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The effects of a root-knot nematode-resistant tomato cultivar and application of the nematicide ethoprop on root-knot nematode injury to cucumber were compared in a tomato-cucumber double-cropping system. A root-knot nematode-resistant tomato cultivar, Celebrity, and a susceptible cultivar, Heatwave, were grown in rotation with cucumber in 1995 and 1996. Celebrity suppressed populations of Meloidogyne incognita in the soil and resulted in a low root-gall rating on the subsequent cucumber crop. Nematode population densities were significantly lower at the termination of the cucumber crop in plots following Celebrity than in plots following Heatwave. Premium and marketable yields of cucumbers were higher in plots following Celebrity than in plots following Heatwave. Application of ethoprop through drip irrigation at 4.6 kg a.i./ha reduced root galling on the cucumber crop but had no effect on the nematode population density in the soil at crop termination. Ethoprop did not affect cucumber yield. These results indicate that planting a resistant tomato cultivar in a tomato-cucumber double-cropping system is more effective than applying ethoprop for managing M. incognita.