Beta Amyloid Peptide: Research Paper : Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate

Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate

Abstract

The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33570950/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial

Discovery of Atabecestat (JNJ-54861911): A Thiazine-Based β-Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor Advanced to the Phase 2b/3 EARLY Clinical Trial

Abstract

Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33588527/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Antibody-Free Determinations of Low-Mass, Soluble Oligomers of Aβ 42 and Aβ 40 by Planar Bilayer Lipid Membrane-Based Electrochemical Biosensor

Antibody-Free Determinations of Low-Mass, Soluble Oligomers of Aβ 42 and Aβ 40 by Planar Bilayer Lipid Membrane-Based Electrochemical Biosensor

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Abnormal aggregates of both β-amyloid peptide (Aβ) subtypes, Aβ42 and Aβ40, are the typical neuropathology hallmarks of AD. However, because of the lack of specific recognition elements such as an antibody and aptamer, it is difficult to differentiate and determine the oligomers of Aβ42 and Aβ40 in clinic. In this paper, we developed a planar bilayer lipid membrane (BLM)-based electrochemical biosensor. According to the dynamic differences on oligomer-induced BLM damage, both low-mass, soluble oligomers of Aβ42 and Aβ40 (L-Aβ42O and L-Aβ40O) were measured in turn by electrochemical impedance spectroscopy. The BLM was supported by a porous 11-mercaptoundecanoic acid layer on a gold electrode, which amplified the impedance signal corresponding to the membrane damage and improved the detection sensitivity. The weakly charged surface of the BLM ensured the low non-specific adsorption of coexisting proteins in cerebrospinal fluid (CSF). Using the electrochemical biosensor, L-Aβ42O was determined within 20 min, with a linear range from 5 to 500 pM and a detection limit of 3 pM. Meanwhile, L-Aβ40O was determined within 60 min, with a linear range from 60 pM to 6.0 nM and a detection limit of 26 pM. The recoveries in oligomer-spiked artificial CSF and human CSF samples confirmed the accuracy and applicability of this proposed method in clinic. This work provides an antibody-free, highly selective, and sensitive method for simultaneous detections of L-Aβ42O and L-Aβ40O in real CSF samples, which is significant for the early diagnosis and prognosis of AD.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33571410/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : MR spectroscopy and imaging-derived measurements in the supplementary motor area for biomarkers of amyotrophic lateral sclerosis

MR spectroscopy and imaging-derived measurements in the supplementary motor area for biomarkers of amyotrophic lateral sclerosis

Abstract

The diagnosis of amyotrophic lateral sclerosis (ALS) requires both upper and lower motor neuron signs. However, quite a few patients with ALS lack the upper motor neuron sign during the disease. This study sought to investigate whether metabolites, including glutamate (Glu), N-acetyl aspartate (NAA), and gamma aminobutyric acid (GABA), in the supplementary motor area (SMA) measured by magnetic resonance spectroscopy (MRS), could be a surrogate biomarker for ALS. Twenty-five patients with ALS and 12 controls underwent 3.0-T MR scanning, which measured Glu, NAA, and GABA. Finally, receiver operating characteristic (ROC) curves were created and the area under curve (AUC) was calculated to assess the diagnostic power. Logistic regression analysis revealed the usefulness of both Glu and NAA for the differentiation of ALS from controls (Glu, P = 0.009; NAA, P = 0.033). The ratio of Glu to NAA or GABA was significantly increased in patients with ALS (Glu/NAA, P = 0.027; Glu/GABA, P = 0.003). Both the AUCs were more than 0.7, with high specificity but low sensitivity. The present findings might indicate that both the Glu/NAA and the Glu/GABA ratios in the SMA could be potential biomarkers for the diagnosis of ALS.

Keywords: Amyotrophic lateral sclerosis; GABA; Glutamate; MRS; N-acetyl aspartate; Supplementary motor area.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33594539/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Anosognosia for memory in dementia with Lewy bodies compared with Alzheimer's disease

Anosognosia for memory in dementia with Lewy bodies compared with Alzheimer's disease

Abstract

Objectives: Anosognosia is the inability to recognize one's own symptoms. Although dementia with Lewy bodies (DLB) is the second most common degenerative dementia, there is little evidence of memory deficit awareness in this condition. The objectives of this research were to compare anosognosia between individuals with DLB and dementia due to Alzheimer's disease (AD) and to evaluate whether medial temporal atrophy, a marker of AD pathology, could help to explain different rates of anosognosia in DLB and dementia due to AD.

Methods/design: This is a cross-sectional study that took place at the Memory Clinic of D'Or Institute for Research and Education (IDOR). Twenty individuals with DLB and 20 with dementia due to AD were included in this study. We assessed anosognosia for memory using an index derived from subjective memory complaints (using the Memory Complaint Questionnaire) and from the performance in memory neuropsychological testing (Rey Auditory Verbal Learning Test). Thirty-one participants also underwent brain Magnetic Resonance Imaging to evaluate hippocampal atrophy with a visual scale (MTA-score [medial temporal atrophy score]).

Results: There was no significant difference between groups regarding age, years of education, sex or time of disease. Individuals with DLB had a higher index of anosognosia than dementia due to AD (2.92 and 1.87; p = 0.024), meaning worse awareness of memory deficits. MTA-score was slightly higher in dementia due to AD than in DLB, albeit without statistical significance.

Conclusion: Our study was the first to demonstrate that anosognosia for memory is worse in DLB than in dementia due to AD. This finding supports the hypothesis that anosognosia in DLB is a heterogeneous phenomenon.

Keywords: Lewy Body disease; anosognosia; dementia.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33594752/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Efficient and Explainable Risk Assessments for Imminent Dementia in an Aging Cohort Study

Efficient and Explainable Risk Assessments for Imminent Dementia in an Aging Cohort Study

Abstract

As the aging US population grows, scalable approaches are needed to identify individuals at risk for dementia. Common prediction tools have limited predictive value, involve expensive neuroimaging, or require extensive and repeated cognitive testing. None of these approaches scale to the sizable aging population who do not receive routine clinical assessments. Our study seeks a tractable and widely administrable set of metrics that can accurately predict imminent (i.e., within three years) dementia onset. To this end, we develop and apply a machine learning (ML) model to an aging cohort study with an extensive set of longitudinal clinical variables to highlight at-risk individuals with better accuracy than standard rudimentary approaches. Next, we reduce the burden needed to achieve accurate risk assessments for those deemed at risk by (1) predicting when consecutive clinical visits may be unnecessary, and (2) selecting a subset of highly predictive cognitive tests. Finally, we demonstrate that our method successfully provides individualized prediction explanations that retain non-linear feature effects present in the data. Our final model, which uses only four cognitive tests (less than 20 minutes to administer) collected in a single visit, affords predictive performance comparable to a standard 100-minute neuropsychological battery and personalized risk explanations. Our approach shows the potential for an efficient tool for screening and explaining dementia risk in the general aging population

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33596178/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives

Outcomes of clinical utility in amyloid-PET studies: state of art and future perspectives

Abstract

Purpose: To review how outcomes of clinical utility are operationalized in current amyloid-PET validation studies, to prepare for formal assessment of clinical utility of amyloid-PET-based diagnosis.

Methods: Systematic review of amyloid-PET research studies published up to April 2020 that included outcomes of clinical utility. We extracted and analyzed (a) outcome categories, (b) their definition, and (c) their methods of assessment.

Results: Thirty-two studies were eligible. (a) Outcome categories were clinician-centered (found in 25/32 studies, 78%), patient-/caregiver-centered (in 9/32 studies, 28%), and health economics-centered (5/32, 16%). (b) Definition: Outcomes were mainly defined by clinical researchers; only the ABIDE study expressly included stakeholders in group discussions. Clinician-centered outcomes mainly consisted of incremental diagnostic value (25/32, 78%) and change in patient management (17/32, 53%); patient-/caregiver-centered outcomes considered distress after amyloid-pet-based diagnosis disclosure (8/32, 25%), including quantified burden of procedure for patients' outcomes (n = 8) (1/8, 12.5%), impact of disclosure of results (6/8, 75%), and psychological implications of biomarker-based diagnosis (75%); and health economics outcomes focused on costs to achieve a high-confidence etiological diagnosis (5/32, 16%) and impact on quality of life (1/32, 3%). (c) Assessment: all outcome categories were operationalized inconsistently across studies, employing 26 different tools without formal rationale for selection.

Conclusion: Current studies validating amyloid-PET already assessed outcomes for clinical utility, although non-clinician-based outcomes were inconsistent. A wider participation of stakeholders may help produce a more thorough and systematic definition and assessment of outcomes of clinical utility and help collect evidence informing decisions on reimbursement of amyloid-PET.

Keywords: Alzheimer's disease; Amyloid-PET; Clinical utility; Diagnostic biomarkers; Outcome; Systematic review.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33594474/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.