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      Combining hippocampal volume metrics to better understand Alzheimer’s disease progression in at-risk individuals

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          Abstract

          To date nearly all clinical trials of Alzheimer’s disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volume (HV) and assess the added benefit of combining HV and rate of hippocampal atrophy over time in relation to disease progression. Following the cross-validation of previously published estimates of the predictive value of HV, we consider a series of combinations of HV metrics and show that a combination of HV and rate of hippocampal atrophy characterises disease progression better than either measure individually. Furthermore, we demonstrate that the risk of disease progression associated with HV metrics does not differ significantly between clinical states. HV and rate of hippocampal atrophy should therefore be used in tandem when describing AD progression in at-risk individuals. Analyses also suggest that the effects of HV metrics are constant across the continuum of the early stages of the disease.

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          Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

          BACKGROUND Alzheimer’s disease is characterized by the deposition of amyloid-beta (A β ) plaques in the brain. A β is produced from the sequential cleavage of amyloid precursor protein by β -site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by y-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the A β level in the cerebrospinal fluid of patients with Alzheimer’s disease. METHODS We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events.(ClinicalTrials.gov [Related object:] .)
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            Anterior temporal lobes and hippocampal formations: normative volumetric measurements from MR images in young adults.

            Volumes of the right and left anterior temporal lobes and hippocampal formations were measured from magnetic resonance images in 52 healthy volunteers, aged 20-40 years. Subjects were selected by age, sex, and handedness to evaluate possible effect of these variables. Data were normalized for variation in total intracranial volume between individuals. Right-left asymmetry in the volumes of the anterior temporal lobes and hippocampal formations was a normal finding. The anterior temporal lobe of the non-dominant (right) hemisphere was larger than the left by a small (mean right-left difference, 2.3 cm3) but statistically significant amount (P less than .005) in right-handed subjects. No significant effect of age or sex was seen in normalized right or left anterior temporal lobe volume. The right hippocampal formation was larger than the left for all subjects by a small (mean right-left difference, 0.3 cm3) but statistically significant amount (P less than .001). No effect of age, sex, or handedness was seen in normalized hippocampal formation volumes.
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              Why do so many clinical trials of therapies for Alzheimer's disease fail?

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                Author and article information

                Contributors
                k.mcrae-mckee@imperial.ac.uk
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                16 May 2019
                16 May 2019
                2019
                : 9
                : 7499
                Affiliations
                [1 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Infectious Disease Epidemiology, , School of Public Health, Faculty of Medicine, Imperial College London, ; St Mary’s Campus, Norfolk Place, W2 1PG London, United Kingdom
                [2 ]Janssen Prevention Center, Archimedesweg 4, 2333 CN Leiden, The Netherlands
                Author information
                http://orcid.org/0000-0001-9476-0462
                http://orcid.org/0000-0001-6166-5899
                Article
                42632
                10.1038/s41598-019-42632-w
                6522521
                31097733
                404333b5-e626-422e-86ce-ab25fa8a52fb
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 August 2018
                : 3 April 2019
                Funding
                Funded by: This study was funded by Janssen Prevention Centre, http://www.janssen.com/janssenprevention-center, funding received by RMA
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized
                predictive markers,alzheimer's disease
                Uncategorized
                predictive markers, alzheimer's disease

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