WEB-BASED SOFTWARE FOR REAL-TIME SIMULATION-ASSISTED TRIAL DESIGN IN ALZHEIMER’S DISEASE

2015 ◽  
pp. 1-4
Author(s):  
D. Polhamus ◽  
J. Kang ◽  
J. Rogers ◽  
M. Gastonguay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Statistical Power ◽  
Operating Characteristics ◽  
Longitudinal Models ◽  
Exclusion Criteria ◽  
Web Based ◽  
Correct Dose ◽  
Time Simulation ◽  
Simulation Based

Clinical trials for Alzheimer’s Disease (AD) are necessarily designed in the presence of substantial quantitative uncertainty. Certain important aspects of this uncertainty can be mitigated by developing longitudinal models for AD progression and by using these models to simulate virtual trials and estimate operating characteristics (such as statistical power, the probability of stopping at an interim analysis, the probability of identifying the correct dose, etc.) as a function of candidate design features, such as inclusion / exclusion criteria. In this brief report we describe the development and deployment of a customized software solution that allows such simulation-based results to be generated “on the fly” in the context of a drug development team meeting. This solution leverages a number of recent practical advances in statistical and scientific computing that could be much more broadly leveraged to assure more quantitatively grounded trial designs in Alzheimer’s Disease.

Identification and Temporal Characterization of Features Associated with the Conversion from Mild Cognitive Impairment to Alzheimer’s Disease

2018 ◽  
Vol 15 (8) ◽  
pp. 751-763 ◽  
Author(s):  
Antonio Martinez-Torteya ◽  
Hugo Gomez-Rueda ◽  
Victor Trevino ◽  
Joshua Farber ◽  
Jose Tamez-Pena ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Neuropsychological Tests ◽  
Quantitative Mri ◽  
Rank Test ◽  
Longitudinal Models ◽  
Log Rank Test ◽  
Medical Histories

Background: Diagnosing Alzheimer’s disease (AD) in its earliest stages is important for therapeutic and support planning. Similarly, being able to predict who will convert from mild cognitive impairment (MCI) to AD would have clinical implications. Objectives: The goals of this study were to identify features from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database associated with the conversion from MCI to AD, and to characterize the temporal evolution of that conversion. Methods: We screened the publically available ADNI longitudinal database for subjects with MCI who have developed AD (cases: n=305), and subjects with MCI who have remained stable (controls: n=250). Analyses included 1,827 features from laboratory assays (n=12), quantitative MRI scans (n=1,423), PET studies (n=136), medical histories (n=72), and neuropsychological tests (n=184). Statistical longitudinal models identified features with significant differences in longitudinal behavior between cases and matched controls. A multiple-comparison adjusted log-rank test identified the capacity of the significant predictive features to predict early conversion. Results: 411 features (22.5%) were found to be statistically different between cases and controls at the time of AD diagnosis; 385 features were statistically different at least 6 months prior to diagnosis, and 28 features distinguished early from late conversion, 20 of which were obtained from neuropsychological tests. In addition, 69 features (3.7%) had statistically significant changes prior to AD diagnosis. Conclusion: Our results characterized features associated with disease progression from MCI to AD, and, in addition, the log-rank test identified features which are associated with the risk of early conversion.

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 Plasma P-tau 181, P-tau 217 and Other Blood-Based Alzheimer's Disease Biomarkers in a Multi-Ethnic, Community Study

2020 ◽  
Author(s):  
Adam M. Brickman ◽  
Jennifer J Manly ◽  
Lawrence Honig ◽  
Danurys Sanchez ◽  
Dolly Reyes-Dumeyer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ethnic Community ◽  
Community Study ◽  
Community Studies ◽  
Operating Characteristics ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Clinical Diagnoses ◽  
Washington Heights

Introduction. Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights, Inwood, Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia. Methods. We measured plasma Aβ40, Aβ42,T-tau, P-tau181 and P-tau217, and neurofilament light chain (NfL) in 113 autopsied participants, (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD. Results. P-tau181, P-tau217 and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased P-tau217 and P-tau181 were associated with subsequent AD diagnosis. Discussion. Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies.

Increasing Diagnostic Accuracy of Mild Cognitive Impairment due to Alzheimer’s Disease by User-Independent, Web-Based Whole-Brain Volumetry

2018 ◽  
Vol 65 (4) ◽  
pp. 1459-1467 ◽  
Author(s):  
Dennis M. Hedderich ◽  
Judith E. Spiro ◽  
Oliver Goldhardt ◽  
Johannes Kaesmacher ◽  
Benedikt Wiestler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Diagnostic Accuracy ◽  
Whole Brain ◽  
Web Based ◽  
Brain Volumetry

Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer’s Disease

2021 ◽  
pp. 1-8
Author(s):  
Marcella Reale ◽  
Claudia Carrarini ◽  
Mirella Russo ◽  
Fedele Dono ◽  
Laura Ferri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Dementia With Lewy Bodies ◽  
Mononuclear Cells ◽  
Lewy Bodies ◽  
Acetylcholinesterase Inhibitors ◽  
Operating Characteristics ◽  
Peripheral Blood Mononuclear

Background: Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. Objective: We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. Methods: Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. Results: Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. Conclusion: Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

scholarly journals MicroRNA-Seq Data Analysis Pipeline to Identify Blood Biomarkers for Alzheimer's Disease from Public Data

2015 ◽  
Vol 10 ◽  
pp. BMI.S25132 ◽  
Author(s):  
Jun-ichi Satoh ◽  
Yoshihiro Kino ◽  
Shumpei Niida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Data Analysis ◽  
Small Rna ◽  
Small Rna Sequencing ◽  
Rna Seq ◽  
Analysis Pipeline ◽  
Web Based ◽  
Public Data ◽  
Data Analysis Pipeline

Background Alzheimer's disease (AD) is the most common cause of dementia with no curative therapy currently available. Establishment of sensitive and non-invasive biomarkers that promote an early diagnosis of AD is crucial for the effective administration of disease-modifying drugs. MicroRNAs (miRNAs) mediate posttranscriptional repression of numerous target genes. Aberrant regulation of miRNA expression is implicated in AD pathogenesis, and circulating miRNAs serve as potential biomarkers for AD. However, data analysis of numerous AD-specific miRNAs derived from small RNA-sequencing (RNA-Seq) is most often laborious. Methods To identify circulating miRNA biomarkers for AD, we reanalyzed a publicly available small RNA-Seq dataset, composed of blood samples derived from 48 AD patients and 22 normal control (NC) subjects, by a simple web-based miRNA data analysis pipeline that combines omiRas and DIANA miRPath. Results By using omiRas, we identified 27 miRNAs expressed differentially between both groups, including upregulation in AD of miR-26b-3p, miR-28–3p, miR-30c-5p, miR-30d-5p, miR-148b-5p, miR-151a-3p, miR-186–5p, miR-425–5p, miR-550a-5p, miR-1468, miR-4781–3p, miR-5001–3p, and miR-6513–3p and downregulation in AD of let-7a-5p, let-7e-5p, let-7f-5p, let-7g-5p, miR-15a-5p, miR-17–3p, miR-29b-3p, miR-98–5p, miR-144–5p, miR-148a-3p, miR-502–3p, miR-660–5p, miR-1294, and miR-3200–3p. DIANA miRPath indicated that miRNA-regulated pathways potentially down– regulated in AD are linked with neuronal synaptic functions, while those upregulated in AD are implicated in cell survival and cellular communication. Conclusions The simple web-based miRNA data analysis pipeline helps us to effortlessly identify candidates for miRNA biomarkers and pathways of AD from the complex small RNA–Seq data.

scholarly journals Early detection of Alzheimer’s disease with a total score of the German CERAD

2010 ◽  
Vol 16 (5) ◽  
pp. 910-920 ◽  
Author(s):  
MICHAEL M. EHRENSPERGER ◽  
MANFRED BERRES ◽  
KIRSTEN I. TAYLOR ◽  
ANDREAS U. MONSCH
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Logistic Regression ◽  
Correct Classification ◽  
Operating Characteristics ◽  
Healthy Control ◽  
Neuropsychological Assessment Battery ◽  
State Examination

AbstractThe goal of the present study was to evaluate the diagnostic discriminability of three different global scores for the German version of the Consortium to Establish a Registry on Alzheimer’s Disease-Neuropsychological Assessment Battery (CERAD-NAB). The CERAD-NAB was administered to 1100 healthy control participants [NC; Mini-Mental State Examination (MMSE) mean = 28.9] and 352 patients with very mild Alzheimer’s disease (AD; MMSE mean = 26.1) at baseline and subsets of participants at follow-up an average of 2.4 (NC) and 1.2 (AD) years later. We calculated the following global scores: Chandler et al.’s (2005) score (summed raw scores), logistic regression on principal components analysis scores (PCA-LR), and logistic regression on demographically corrected CERAD-NAB variables (LR). Correct classification rates (CCR) were compared with areas under the receiver operating characteristics curves (AUC). The CCR of the LR score (AUC = .976) exceeded that of the PCA-LR, while the PCA-LR (AUC = .968) and Chandler (AUC = .968) scores performed comparably. Retest data improved the CCR of the PCA-LR and Chandler (trend) scores. Thus, for the German CERAD-NAB, Chandler et al.’s total score provided an effective global measure of cognitive functioning, whereby the inclusion of retest data tended to improve correct classification of individual cases. (JINS, 2010, 16, 910–920.)

The Tower of London Test: Different Scoring Criteria for Diagnosing Alzheimer's Disease and Mild Cognitive Impairment

2012 ◽  
Vol 110 (2) ◽  
pp. 477-488 ◽  
Author(s):  
Jonas Jardim de Paula ◽  
Lafaiete Moreira ◽  
Rodrigo Nicolato ◽  
Luiz Armando De Marco ◽  
Humberto Côrrea ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Multinomial Logistic Regression ◽  
Screening Tests ◽  
Scoring Methods ◽  
Operating Characteristics ◽  
Tower Of London ◽  
Characteristics Analysis

The Tower of London (TOL) is used for evaluating planning skills, which is a component of the executive functions. Different versions and scoring criteria were developed for this task, and some of them present with different psychometrical properties. This study aimed to evaluate two specific scoring methods of the TOL in diagnosing Mild Cognitive Impairment and probable Alzheimer's disease. The TOL total scores from 60 patients of each diagnosis were compared with the performance of 60 healthy-aged controls using receiver operating characteristics analysis and multinomial logistic regression. Krikorian method better diagnosed Alzheimer's disease, while Portellas's was better at discriminating healthy controls from Mild Cognitive Impairment, but were not efficient at comparing this last group with Alzheimer's patients. Regression analysis indicates that in addition to screening tests, TOL improves the classification of the three groups. The results suggest the two scoring methods used for this task may be useful for different diagnostic purposes.

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