Performance of Validated MicroRNA Biomarkers for Alzheimer’s Disease in Mild Cognitive Impairment

2020 ◽  
Vol 78 (1) ◽  
pp. 245-263
Author(s):  
Ursula S. Sandau ◽  
Jack T. Wiedrick ◽  
Sierra J. Smith ◽  
Trevor J. McFarland ◽  
Theresa A. Lusardi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage ◽  
Linear Trend ◽  
Area Under The Curve ◽  
Classification Performance ◽  
T Tau ◽  
Median Expression

Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOE ɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

scholarly journals To Explore the Predictive Power of Visuomotor Network Dysfunctions in Mild Cognitive Impairment and Alzheimer’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Justine Staal ◽  
Francesco Mattace-Raso ◽  
Hennie A. M. Daniels ◽  
Johannes van der Steen ◽  
Johan J. M. Pel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Support Vector Machine ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Predictive Power ◽  
Area Under The Curve ◽  
Classification Performance ◽  
Support Vector ◽  
Potential Biomarker

BackgroundResearch into Alzheimer’s disease has shifted toward the identification of minimally invasive and less time-consuming modalities to define preclinical stages of Alzheimer’s disease.MethodHere, we propose visuomotor network dysfunctions as a potential biomarker in AD and its prodromal stage, mild cognitive impairment with underlying the Alzheimer’s disease pathology. The functionality of this network was tested in terms of timing, accuracy, and speed with goal-directed eye-hand tasks. The predictive power was determined by comparing the classification performance of a zero-rule algorithm (baseline), a decision tree, a support vector machine, and a neural network using functional parameters to classify controls without cognitive disorders, mild cognitive impaired patients, and Alzheimer’s disease patients.ResultsFair to good classification was achieved between controls and patients, controls and mild cognitive impaired patients, and between controls and Alzheimer’s disease patients with the support vector machine (77–82% accuracy, 57–93% sensitivity, 63–90% specificity, 0.74–0.78 area under the curve). Classification between mild cognitive impaired patients and Alzheimer’s disease patients was poor, as no algorithm outperformed the baseline (63% accuracy, 0% sensitivity, 100% specificity, 0.50 area under the curve).Comparison with Existing Method(s)The classification performance found in the present study is comparable to that of the existing CSF and MRI biomarkers.ConclusionThe data suggest that visuomotor network dysfunctions have potential in biomarker research and the proposed eye-hand tasks could add to existing tests to form a clear definition of the preclinical phenotype of AD.

scholarly journals Detection of mild cognitive impairment and early stage dementia with an audio-recorded cognitive scale

2013 ◽  
Vol 25 (8) ◽  
pp. 1325-1333 ◽  
Author(s):  
Margaret C. Sewell ◽  
Xiaodong Luo ◽  
Judith Neugroschl ◽  
Mary Sano
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Verbal Memory ◽  
Early Stage ◽  
Neuropsychological Testing ◽  
Area Under The Curve ◽  
Cognitive Domain ◽  
Screening Measures

ABSTRACTBackground: Physicians often miss diagnosis of mild cognitive impairment (MCI) or early dementia and screening measures can be insensitive to very mild impairments. Other cognitive assessments may take too much time or be frustrating to seniors. This study examined the ability of an audio-recorded scale, developed in Australia, to detect MCI or mild Alzheimer's disease (AD) and compared cognitive domain-specific performance on the audio-recorded scale to in-person battery and common cognitive screens.Method: Seventy-six patients from the Mount Sinai Alzheimer's Disease Research Center were recruited. Patients were aged 75 years or older, with clinical diagnosis of AD or MCI (n = 51) or normal control (n = 25). Participants underwent in-person neuropsychological testing followed by testing with the audio-recorded cognitive screen (ARCS).Results: ARCS provided better discrimination between normal and impaired elderly individuals than either the Mini-Mental State Examination or the clock drawing test. The in-person battery and ARCS analogous variables were significantly correlated, most in the 0.4 to 0.7 range, including verbal memory, executive function/attention, naming, and verbal fluency. The area under the curve generated from the receiver operating characteristic curves indicated high and equivalent discrimination for ARCS and the in-person battery (0.972 vs. 0.988; p = 0.23).Conclusion: The ARCS demonstrated better discrimination between normal controls and those with mild deficits than typical screening measures. Performance on cognitive domains within the ARCS was well correlated with the in-person battery. Completion of the ARCS was accomplished despite mild difficulty hearing the instructions even in very elderly participants, indicating that it may be a useful measure in primary care settings.

scholarly journals Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

2020 ◽  
pp. 1-10
Author(s):  
Christopher Gonzalez ◽  
Nicole S. Tommasi ◽  
Danielle Briggs ◽  
Michael J. Properzi ◽  
Rebecca E. Amariglio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage ◽  
Cognitively Normal ◽  
Financial Capacity ◽  
Posterior Cingulate ◽  
Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p <  0.001; inferior temporal: p <  0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p <  0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p <  0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

P2-009: The chemokines IL8 and MIP-1b distinguish mild cognitive impairment from early stage Alzheimer's disease

2012 ◽  
Vol 8 (4S_Part_7) ◽  
pp. P266-P267
Author(s):  
Milene Gonçalves ◽  
Isabel Santana ◽  
Natália Francisco ◽  
Catarina Cunha ◽  
Sonia Batista ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage

scholarly journals 12-year prediction of mild cognitive impairment aided by Alzheimer’s brain signatures at mean age 56

2021 ◽  
Author(s):  
McKenna E Williams ◽  
Jeremy A Elman ◽  
Linda K McEvoy ◽  
Ole A Andreassen ◽  
Anders M Dale ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Mean Diffusivity ◽  
Area Under The Curve ◽  
Polygenic Risk Score ◽  
Age Difference ◽  
Cognitively Normal ◽  
Brain Age

Abstract Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer’s disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Toward that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: 1) a validated MRI-derived Alzheimer’s disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and 2) a novel gray matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246–367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51–60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer’s disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61–71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply aging-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P=0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently-derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step toward improving very early identification of Alzheimer’s disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

Happy and Sad Judgements in Dependence on Mode and Note Density in Patients with Mild Cognitive Impairment and Early-Stage Alzheimer's Disease

Gerontology ◽  
2014 ◽  
Vol 60 (5) ◽  
pp. 402-412 ◽  
Author(s):  
Manuela Kerer ◽  
Josef Marksteiner ◽  
Hartmann Hinterhuber ◽  
Georg Kemmler ◽  
Harald R. Bliem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage

scholarly journals 0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A23-A23
Author(s):  
R Mehra ◽  
R Bhambra ◽  
J Bena ◽  
L Bekris ◽  
J Leverenz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Csf Biomarkers ◽  
Significance Level ◽  
Unit Increase ◽  
T Tau ◽  
Age And Sex

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

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