Apathy in patients with Alzheimer's disease is a cost-driving factor.

BACKGROUND Apathy is the most frequent neuropsychiatric symptom in patients with dementia of the Alzheimer's type (DAT). We analyzed the influence of apathy on the resource use of DAT patients and their caregivers. METHODS Included were baseline data of 107 DAT patients from a randomized clinical trial on apathy treatment. The Resource Utilization in Dementia (RUD) instrument assessed costs over a 1-month period prior to baseline. Cost predictors were determined via a least absolute shrinkage and selection operator (LASSO). RESULTS On average, total monthly costs were €3070, of which €2711 accounted for caregivers' and €359 for patients' costs. An increase of one point in the Apathy Evaluation Scale resulted in a 4.1% increase in total costs. DISCUSSION Apathy is a significant cost driving factor for total costs in mild to moderate DAT. Effective treatment of apathy might be associated with reduced overall costs in DAT

Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Surface tension and density data for Fe–Cr–Mo, Fe–Cr–Ni, and Fe–Cr–Mn–Ni steels

The temperature dependence of surface tension and density for Fe–Cr–Mo (AISI 4142), Fe–Cr–Ni (AISI 304), and Fe–Cr–Mn–Ni TRIP/TWIP high-manganese (16 wt% Cr, 7 wt% Mn, and 3–9 wt% Ni) liquid alloys are investigated using the conventional maximum bubble pressure (MBP) and sessile drop (SD) methods. In addition, the surface tension of liquid steel is measured using the oscillating droplet method on electromagnetically levitated (EML) liquid droplets at the German Aerospace Centre (DLR, Cologne). The data of thermophysical properties for Fe–Cr–Mn–Ni is of major importance for modeling of infiltration and gas atomization processes in the prototyping of a ‘‘TRIP-Matrix-Composite.’’ The surface tension of TRIP/TWIP steel increased with an increase in temperature in MBP as well as in SD measurement. The manganese evaporation with the conventional measurement methods is not significantly high within the experiments (DMn\0.5 %). The temperature coefficient of surface tension (dr/dT) is positive for liquid steel samples, which can be explained by the concentration of surface active elements. A slight influence of nickel on the surface tension of Fe–Cr–Mn–Ni steel was experimentally observed where r is decreased with increasing nickel content. EML measurement of high-manganese steel, however, is limited to the undercooling state of the liquid steel. The manganese evaporation strongly increased in excess of the liquidus temperature in levitation measurements and a mass loss of droplet of 5 % was observed

Identification of a Cascade of Changes in Activities of Daily Living Preceding Short-Term Clinical Deterioration in Mild Alzheimer's Disease Dementia via Lead-Lag Analysis

Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer's disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer's dementia (AD; MMSE= 23.9 +/- 2.88) were followed at 12 and 24 months. Leadlag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 neuropsychological subtest scores from the CERAD+ test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Delta MMSE 5.8 +/- 8.64; Delta CDR-SOB 4.32 +/- 4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures

A Robust High Throughput Platform to Generate Functional Recombinant Monoclonal Antibodies Using Rabbit B Cells from Peripheral Blood

<div><p>We have developed a robust platform to generate and functionally characterize rabbit-derived antibodies using B cells from peripheral blood. The rapid high throughput procedure generates a diverse set of antibodies, yet requires only few animals to be immunized without the need to sacrifice them. The workflow includes (i) the identification and isolation of single B cells from rabbit blood expressing IgG antibodies, (ii) an elaborate short term B-cell cultivation to produce sufficient monoclonal antigen specific IgG for comprehensive phenotype screens, (iii) the isolation of VH and VL coding regions via PCR from B-cell clones producing antigen specific and functional antibodies followed by the sequence determination, and (iv) the recombinant expression and purification of IgG antibodies. The fully integrated and to a large degree automated platform (demonstrated in this paper using IL1RL1 immunized rabbits) yielded clonal and very diverse IL1RL1-specific and functional IL1RL1-inhibiting rabbit antibodies. These functional IgGs from individual animals were obtained at a short time range after immunization and could be identified already during primary screening, thus substantially lowering the workload for the subsequent B-cell PCR workflow. Early availability of sequence information permits one to select early-on function- and sequence-diverse antibodies for further characterization. In summary, this powerful technology platform has proven to be an efficient and robust method for the rapid generation of antigen specific and functional monoclonal rabbit antibodies without sacrificing the immunized animal.</p></div

Concordance of VL and VH sequences of single <i>E. coli</i> colonies derived from pool-cloning shown for 8 different B-cell clones (ASCs).

<p>Concordance of VL and VH sequences of single <i>E. coli</i> colonies derived from pool-cloning shown for 8 different B-cell clones (ASCs).</p

Bupropion for the Treatment of Apathy in Alzheimer Disease A Randomized Clinical Trial

This randomized clinical trial examines the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Importance Apathy is a frequent neuropsychiatric symptom in dementia of Alzheimer type and negatively affects the disease course and patients' and caregivers' quality of life. Effective treatment options are needed. Objective To examine the efficacy and safety of the dopamine and noradrenaline reuptake inhibitor bupropion in the treatment of apathy in patients with dementia of Alzheimer type. Design, Setting, and Participants This 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial was conducted in a psychiatric and neurological outpatient setting between July 2010 and July 2014 in Germany. Patients with mild-to-moderate dementia of Alzheimer type and clinically relevant apathy were included. Patients with additional clinically relevant depressed mood were excluded. Data analyses were performed between August 2018 and August 2019. Interventions Patients received either bupropion or placebo (150 mg for 4 weeks plus 300 mg for 8 weeks). In case of intolerability of 300 mg, patients continued to receive 150 mg throughout the study. Main Outcomes and Measures Change on the Apathy Evaluation Scale-Clinician Version (AES-C) (score range, 18-72 points) between baseline and week 12 was the primary outcome parameter. Secondary outcome parameters included measures of neuropsychiatric symptoms, cognition, activities of daily living, and quality of life. Outcome measures were assessed at baseline and at 4, 8, and 12 weeks. Results A total of 108 patients (mean [SD] age, 74.8 [5.9] years; 67 men [62%]) were included in the intention-to-treat analysis, with 54 randomized to receive bupropion and 54 randomized to receive placebo. The baseline AES-C score was comparable between the bupropion group and the placebo group (mean [SD], 52.2 [8.7] vs 50.4 [8.2]). After controlling for the baseline AES-C score, site, and comedication with donepezil or galantamine, the mean change in the AES-C score between the bupropion and placebo groups was not statistically significant (mean change, 2.22; 95% CI, -0.47 to 4.91; P = .11). Results on secondary outcomes showed statistically significant differences between bupropion and placebo in terms of total neuropsychiatric symptoms (mean change, 5.52; 95% CI, 2.00 to 9.04; P = .003) and health-related quality of life (uncorrected for multiple comparisons; mean change, -1.66; 95% CI, -3.01 to -0.31; P = .02) with greater improvement in the placebo group. No statistically significant changes between groups were found for activities of daily living (mean change, -2.92; 95% CI, -5.89 to 0.06; P = .05) and cognition (mean change, -0.27; 95% CI, -3.26 to 2.73; P = .86). The numbers of adverse events (bupropion group, 39 patients [72.2%]; placebo group, 33 patients [61.1%]) and serious adverse events (bupropion group, 5 patients [9.3%]; placebo group, 2 patients [3.7%]) were comparable between groups. Conclusions and Relevance Although it is safe, bupropion was not superior to placebo for the treatment of apathy in patients with dementia of Alzheimer type in the absence of clinically relevant depressed mood. Question Is bupropion an effective and safe treatment for apathy in nondepressed patients with dementia of Alzheimer type? Findings In this 12-week, multicenter, double-blind, placebo-controlled, randomized clinical trial, 54 patients received bupropion and 54 received placebo. The mean change in the Apathy Evaluation Scale-Clinician Version score was not statistically significant between the treatment groups. Meaning Bupropion did not improve apathy in patients with dementia of Alzheimer type without depressed mood

Functionality and sequence diversity of the recombinant antibodies per animals and bleeds.

*<p>”Functional” refers to the biochemical IL1RL1:IL33 inhibition assay with a cut off of ≥40% inhibition.</p

Results of the primary screening using primary supernatants (SN) of the B-Cell Cloning workflow containing monoclonal rabbit antibodies.

<p>The statistically confirmed thresholds were rabbit IgG >0.013 µg/ml, human IL1RL1 binding >OD (optical density) 0.195, human Fc binding ≤OD 0.125, cynomolgus IL1RL1 binding >OD 0.184, murine IL1RL1 binding >OD 0.164, and biochemical human IL1RL1:IL33 inhibition ≥40%.</p

Yield of IL1RL1-specific rabbit antibodies.

<p>Scatter Plots depicting the yield of the primary screening using all 7644 supernatants: (<b>A</b>) Human IL1RL1 binding (unit: optical density (OD)) versus IgG concentration; (<b>B</b>) human IL1RL1 binding versus cynomolgus IL1RL1 binding or versus (<b>C</b>) murine IL1RL1 binding. Scatter Plot showing the correlation of the biochemical inhibition assay with the cellular inhibition assay: (<b>D</b>) Threshold ≥40% inhibition, RSq: 0.36, (<b>E</b>) magnification of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0086184#pone-0086184-g003" target="_blank">Figure 3D</a> using the threshold of >90% inhibition, RSq: 0.9. The statistically confirmed cut off values for the calculation of the percentages were as follows: rabbit IgG-positive >0.013 µg/ml, human IL1RL1-positive >OD 0.195, human Fc-positive ≤OD 0.125, cynomolgus IL1RL1-positive >OD 0.184, murine IL1RL1-positive >OD 0.164. Green are the supernatants deriving from the pre-incubation only scenario and red are the SN after the protein panning step. The diamond, the circle and the cross indicate the three different animals. (<b>F</b>) Result of the two dimensional binding matrix identifying different binding epitopes on human IL1RL1. The colored numbers indicate different antigen specific antibodies. The black numbers describe the three antibody groups. The degree of antibody competition in the matrix is depicted by a 3-colour scale with green, black, red color indicating highest competition, mid or lowest competition, respectively.</p