scholarly journals Seeking a New Paradigm for Alzheimer’s Disease: Considering the Roles of Inflammation, Blood-Brain Barrier Dysfunction, and Prion Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-6
Author(s):  
Mark E. McCaulley ◽  
Kira A. Grush
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Disease ◽  
Effective Means ◽  
Neurovascular Unit ◽  
New Paradigm ◽  
Barrier Dysfunction ◽  
Effective Prophylaxis ◽  
Research Findings ◽  
Current Paradigm

There is no effective etiologic treatment for Alzheimer’s disease, nor is there a prophylactic medication which delays or prevents its onset. The lack of an accurate paradigm is undoubtedly related to the lack of effective means of prophylaxis and treatment. The current paradigm of beta amyloid in Alzheimer’s brains causing cognitive dysfunction must be modified. Despite failed clinical trials, research continues into amyloid-oriented treatments. The persistence of the amyloid hypothesis/paradigm is an example of anchoring and representativeness heuristics described by Kahneman and Tversky in their classic 1974 Science paper. Economic factors also contribute to the persistence of this paradigm. Paradigms impact the scientific process by the following: (1) what is studied; (2) the types of questions that are asked; (3) the structure and nature of the questions; (4) the interpretations of research findings. We review the contribution of inflammation, malfunction of the neurovascular unit, and prion disease to Alzheimer’s disease manifestations. Any or all of these are candidates for inclusion into a more accurate, inclusive, and useful new paradigm. By incorporating emerging facts and understanding into a new paradigm, we will enhance our ability to move toward effective prophylaxis and therapy for this tragic disease.

scholarly journals Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

2013 ◽  
Vol 33 (10) ◽  
pp. 1500-1513 ◽  
Author(s):  
Michelle A Erickson ◽  
William A Banks
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Potential Contribution ◽  
Barrier Dysfunction ◽  
Blood Brain ◽  
Amyloid Cascade

The blood–brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-β (Aβ) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Aβ pathology.

The Dissemination of Research Findings: Some Limitations Revealed When Attempting a Meta-Analysis

1986 ◽  
Vol 20 (3) ◽  
pp. 384-385 ◽  
Author(s):  
A. F. Jorm
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Meta Analysis ◽  
Descriptive Statistics ◽  
Additional Information ◽  
Dissemination Of Research ◽  
Drug Treatments ◽  
Research Findings

A meta-analysis of the literature on drug treatments for Alzheimer's disease revealed the following limitations in the dissemination of research findings: multiple publication of findings, failure to report basic descriptive statistics and failure to respond to written requests for additional information on the research. The possible reasons for these problems and remedies for them are discussed.

scholarly journals RECRUITMENT INTO THE ALZHEIMER PREVENTION TRIALS (APT) WEBSTUDY FOR A TRIAL-READY COHORT FOR PRECLINICAL AND PRODROMAL ALZHEIMER’S DISEASE (TRCPAD)

2020 ◽  
pp. 1-7
Author(s):  
S. Walter ◽  
T.B. Clanton ◽  
O.G. Langford ◽  
M.S. Rafii ◽  
E.J. Shaffer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Effective Means ◽  
Web Based ◽  
The Us ◽  
Study Team ◽  
Prodromal Alzheimer’S Disease ◽  
Prevention Trials ◽  
Study Participants ◽  
The Impact

BACKGROUND: The Alzheimer Prevention Trials (APT) Webstudy is the first stage in establishing a Trial-ready Cohort for Preclinical and Prodromal Alzheimer’s disease (TRC-PAD). This paper describes recruitment approaches for the APT Webstudy. Objectives: To remotely enroll a cohort of individuals into a web-based longitudinal observational study. Participants are followed quarterly with brief cognitive and functional assessments, and referred to Sites for in-clinic testing and biomarker confirmation prior to enrolling in the Trial-ready Cohort (TRC). Design: Participants are referred to the APT Webstudy from existing registries of individuals interested in brain health and Alzheimer’s disease research, as well as through central and site recruitment efforts. The study team utilizes Urchin Tracking Modules (UTM) codes to better understand the impact of electronic recruitment methods. Setting: A remotely enrolled online study. Participants: Volunteers who are at least 50 years old and interested in Alzheimer’s research. Measurements: Demographics and recruitment source of participant where measured by UTM. Results: 30,650 participants consented to the APT Webstudy as of April 2020, with 69.7% resulting from referrals from online registries. Emails sent by the registry to participants were the most effective means of recruitment. Participants are distributed across the US, and the demographics of the APT Webstudy reflect the referral registries, with 73.1% female, 85.0% highly educated, and 92.5% Caucasian. Conclusions: We have demonstrated the feasibility of enrolling a remote web-based study utilizing existing registries as a primary referral source. The next priority of the study team is to engage in recruitment initiatives that will improve the diversity of the cohort, towards the goal of clinical trials that better represent the US population.

scholarly journals Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

2020 ◽  
Author(s):  
Betty M. Tijms ◽  
Johan Gobom ◽  
Lianne Reus ◽  
Iris Jansen ◽  
Shengjun Hong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Innate Immune ◽  
Barrier Dysfunction ◽  
Physiological Processes ◽  
Increased Risk ◽  
Biological Heterogeneity ◽  
Subtype 3 ◽  
Non Negative Matrix Factorization

AbstractAlzheimer’s disease (AD) is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. Cerebrospinal fluid (CSF) contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether AD biological subtypes can be detected in cerebrospinal fluid (CSF) proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 913 tested) proteins differed between AD (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and intact cognition, n=127). Using these proteins for data-driven clustering, we identified within each cohorts three robust pathophysiological AD subtypes showing 1) hyperplasticity and increased BACE1 levels; 2) innate immune activation; and 3) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals was labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for AD (all p>0.01). Additional pathological comparisons that were available for a subset in ADNI only further showed that subtypes showed similar severity of AD pathology, and did not differ in the frequencies of co-pathologies, providing further support that these differences truly reflect AD heterogeneity. Compared to controls all non-demented AD individuals had increased risk to show clinical progression, and compared to subtype 1, subtype 2 showed faster progression to after correcting for age, sex, level of education and tau levels (HR (95%CI) subtype 2 vs 1 = 2.5 (1.2, 5.1), p = 0.01), and subtype 3 at trend level (HR (95%CI) = 2.1 (1.0, 4.4)). Together, these results demonstrate the value of CSF proteomics to study biological heterogeneity in AD patients, and suggest that subtypes may require tailored therapy.

scholarly journals Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Dong Wang ◽  
Fanglian Chen ◽  
Zhaoli Han ◽  
Zhenyu Yin ◽  
Xintong Ge ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Factors Affecting ◽  
Blood Brain ◽  
Normal Metabolism

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer’s disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood–brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

Research on Computer-Aided Diagnosis of Alzheimer’s Disease Based on Heterogeneous Medical Data Fusion

2019 ◽  
Vol 33 (05) ◽  
pp. 1957001
Author(s):  
Yin Dai ◽  
Daoyun Qiu ◽  
Yang Wang ◽  
Sizhe Dong ◽  
Hong-Li Wang
Keyword(s):  
Neural Network ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Convolutional Neural Network ◽  
Effective Means ◽  
Computer Aided Diagnosis ◽  
Test Results ◽  
Back Propagation Algorithm ◽  
Computer Aided ◽  
Aided Diagnosis

Alzheimer’s disease is the third most expensive disease, only after cancer and cardiopathy. It is also the fourth leading cause of death in the elderly after cardiopathy, cancer, and cerebral palsy. The disease lacks specific diagnostic criteria. At present, there is still no definitive and effective means for preclinical diagnosis and treatment. It is the only disease that cannot be prevented and cured among the world’s top ten fatal diseases. It has now been proposed as a global issue. Computer-aided diagnosis of Alzheimer’s disease (AD) is mostly based on images at this stage. This project uses multi-modality imaging MRI/PET combining with clinical scales and uses deep learning-based computer-aided diagnosis to treat AD, improves the comprehensiveness and accuracy of diagnosis. The project uses Bayesian model and convolutional neural network to train experimental data. The experiment uses the improved existing network model, LeNet-5, to design and build a 10-layer convolutional neural network. The network uses a back-propagation algorithm based on a gradient descent strategy to achieve good diagnostic results. Through the calculation of sensitivity, specificity and accuracy, the test results were evaluated, good test results were obtained.

Statins have therapeutic potential for the treatment of Alzheimer's disease, likely via protection of the neurovascular unit in the AD brain

2012 ◽  
Vol 322 (1-2) ◽  
pp. 59-63 ◽  
Author(s):  
Tomoko Kurata ◽  
Hiromi Kawai ◽  
Kazunori Miyazaki ◽  
Miki Kozuki ◽  
Nobutoshi Morimoto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Neurovascular Unit
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