scholarly journals Comparison of subtyping methods for neuroimaging studies in Alzheimer’s disease: a call for harmonization

2020 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Gustav Mårtensson ◽  
Konstantinos Poulakis ◽  
J-Sebastian Muehlboeck ◽  
Elena Rodriguez-Vieitez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Reference Group ◽  
Group Level ◽  
Healthy Individuals ◽  
Individual Level ◽  
Dementia Patients ◽  
Tau Pet ◽  
The Individual

Abstract Biological subtypes in Alzheimer’s disease, originally identified on neuropathological data, have been translated to in vivo biomarkers such as structural magnetic resonance imaging (sMRI) and positron emission tomography (PET), to disentangle the heterogeneity within Alzheimer’s disease. Although there is methodological variability across studies, comparable characteristics of subtypes are reported at the group level. In this study, we investigated whether group-level similarities translate to individual-level agreement across subtyping methods, in a head-to-head context. We compared five previously published subtyping methods. Firstly, we validated the subtyping methods in 89 amyloid-beta positive Alzheimer’s disease dementia patients (reference group: 70 amyloid-beta negative healthy individuals) using sMRI. Secondly, we extended and applied the subtyping methods to 53 amyloid-beta positive prodromal Alzheimer’s disease and 30 amyloid-beta positive Alzheimer’s disease dementia patients (reference group: 200 amyloid-beta negative healthy individuals) using sMRI and tau PET. Subtyping methods were implemented as outlined in each original study. Group-level and individual-level comparisons across methods were performed. Each individual subtyping method was replicated, and the proof-of-concept was established. At the group level, all methods captured subtypes with similar patterns of demographic and clinical characteristics, and with similar cortical thinning and tau PET uptake patterns. However, at the individual level large disagreements were found in subtype assignments. Although characteristics of subtypes are comparable at the group level, there is a large disagreement at the individual level across subtyping methods. Therefore, there is an urgent need for consensus and harmonization across subtyping methods. We call for establishment of an open benchmarking framework to overcome this problem.

scholarly journals Towards harmonizing subtyping methods for neuroimaging studies in Alzheimer’s disease

2020 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Gustav Mårtensson ◽  
Konstantinos Poulakis ◽  
J-Sebastian Muehlboeck ◽  
Elena Rodriguez-Vieitez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Reference Group ◽  
Group Level ◽  
Individual Level ◽  
Dementia Patients ◽  
Positron Emission ◽  
Tau Pet ◽  
The Individual

ABSTRACTBackgroundBiological subtypes in Alzheimer’s disease (AD), originally identified on neuropathological data, have been translated to in vivo biomarkers such as structural magnetic resonance imaging (sMRI) and positron emission tomography (PET), to disentangle the heterogeneity within AD. Although there is methodological variability across studies, comparable characteristics of subtypes are reported at the group level. In this study, we investigated whether group-level similarities translate to individual-level agreement across subtyping methods, in a head-to-head context.MethodsWe compared five previously published subtyping methods. Firstly, we validated the subtyping methods in 89 amyloid-beta positive (Aβ+) AD dementia patients (reference group: 70 Aβ-healthy individuals; HC) using sMRI. Secondly, we extended and applied the subtyping methods to 53 Aβ+ prodromal AD and 30 Aβ+ AD dementia patients (reference group: 200 Aβ-HC) using both sMRI and tau PET. Subtyping methods were implemented as outlined in each original study. Group-level and individual-level comparisons across methods were performed.ResultsEach individual method was replicated and the proof-of-concept was established. All methods captured subtypes with similar patterns of demographic and clinical characteristics, and with similar maps of cortical thinning and tau PET uptake, at the group level. However, large disagreements were found at the individual level.ConclusionsAlthough characteristics of subtypes may be comparable at the group level, there is a large disagreement at the individual level across subtyping methods. Therefore, there is an urgent need for consensus and harmonization across subtyping methods. We call for establishment of an open benchmarking framework to overcome this problem.

scholarly journals Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer's disease

2021 ◽  
Author(s):  
Elizabeth Levitis ◽  
Jacob W Vogel ◽  
Thomas Funck ◽  
Vladimir Halchinski ◽  
Serge Gauthier ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Pattern ◽  
Amyloid Beta ◽  
Large Scale ◽  
Autosomal Dominant ◽  
Model Performance ◽  
Sporadic Alzheimer’S Disease ◽  
Individual Level ◽  
Data Driven Approach

Amyloid-beta (Aβ) deposition is one of the hallmark pathologies in both sporadic Alzheimer's disease (sAD) and autosomal dominant Alzheimer's disease (ADAD), the latter of which is caused by mutations in genes involved in Aβ processing. Despite Aβ deposition being a centerpiece to both sAD and ADAD, some differences between these AD subtypes have been observed with respect to the spatial pattern of Aβ. Previous work has shown that the spatial pattern of Aβ in individuals spanning the sAD spectrum can be reproduced with high accuracy using an epidemic spreading model (ESM), which simulates the diffusion of Aβ across neuronal connections and is constrained by individual rates of Aβ production and clearance. However, it has not been investigated whether Aβ deposition in the rarer ADAD can be modeled in the same way, and if so, how congruent the spreading patterns of Aβ across sAD and ADAD are. We leverage the ESM as a data-driven approach to probe individual-level variation in the spreading patterns of Aβ across three different large-scale imaging datasets (2 SAD, 1 ADAD). We applied the ESM separately to the Alzheimer's Disease Neuroimaging initiative (N=737), the Open Access Series of Imaging Studies (N=510), and the Dominantly Inherited Alzheimer's Network (N=249), the latter two of which were processed using an identical pipeline. We assessed inter- and intra-individual model performance in each dataset separately, and further identified the most likely epicenter of Aβ spread for each individual. Using epicenters defined in previous work in sAD, the ESM provided moderate prediction of the regional pattern of Aβ deposition across all three datasets. We further find that, while the most likely epicenter for most Aβ-positive subjects overlaps with the default mode network, 13% of ADAD individuals were best characterized by a striatal origin of Aβ spread. These subjects were also distinguished by being younger than ADAD subjects with a DMN Aβ origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most ADAD patients express Aβ spreading patters similar to those of sAD, but that there may be a subset of ADAD patients with a separate, striatal phenotype.

scholarly journals Serum MicroRNA Profiles Serve as Novel Biomarkers for the Diagnosis of Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Hui Dong ◽  
Jialu Li ◽  
Lei Huang ◽  
Xi Chen ◽  
Donghai Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Characteristic Curve ◽  
Serum Samples ◽  
Individual Level ◽  
Serum Microrna ◽  
Serum Mirnas ◽  
Potential Biomarker ◽  
Novel Biomarkers ◽  
The Individual

Alzheimer’s disease (AD) is the most common type of dementia, and promptly diagnosis of AD is crucial for delaying the development of disease and improving patient quality of life. However, AD detection, particularly in the early stages, remains a substantial challenge due to the lack of specific biomarkers. The present study was undertaken to identify and validate the potential of circulating miRNAs as novel biomarkers for AD. Solexa sequencing was employed to screen the expression profile of serum miRNAs in AD and controls. RT-qPCR was used to confirm the altered miRNAs at the individual level. Moreover, candidate miRNAs were examined in the serum samples of patients with mild cognitive impairment (MCI) and vascular dementia (VD). The results showed that four miRNAs (miR-31, miR-93, miR-143, and miR-146a) were markedly decreased in AD patients’ serum compared with controls. Receiver operating characteristic curve analysis demonstrated that this panel of four miRNAs could be used as potential biomarker for AD. Furthermore, miR-93, and miR-146a were significantly elevated in MCI compared with controls, and the panel of miR-31, miR-93 and miR-146a can be used to discriminate AD from VD. We established a panel of four serum miRNAs as a novel noninvasive biomarker for AD diagnosis.

scholarly journals Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative

2020 ◽  
Author(s):  
Thomas K Karikari ◽  
Andréa L. Benedet ◽  
Nicholas J Ashton ◽  
Juan Lantero Rodriguez ◽  
Anniina Snellman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Clinical Stage ◽  
Individual Variability ◽  
Non Invasive ◽  
Longitudinal Measurements ◽  
Dementia Patients ◽  
Positron Emission ◽  
Pet Scans

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-beta and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral amyloid-beta and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1,000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by amyloid-beta PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative amyloid-beta PET scans did not show increased plasma p-tau181. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4%-89.2%), as well as to distinguish between amyloid-beta-negative and amyloid-beta-positive individuals along the Alzheimer's continuum (AUC=76.9%; 95% CI, 74.0%-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

scholarly journals Associations between different tau-PET patterns and longitudinal atrophy in the Alzheimer's disease continuum

2021 ◽  
Author(s):  
Rosaleena Mohanty ◽  
Daniel Ferreira ◽  
Agneta Nordberg ◽  
Eric Westman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Structural Mri ◽  
Tau Pathology ◽  
Discrete Subgroups ◽  
Cognitively Normal ◽  
Prodromal Ad ◽  
Tau Pet ◽  
The Relationship

INTRODUCTION: Different subtypes/patterns have been defined using tau-PET and structural-MRI in Alzheimer's disease (AD), but the relationship between tau pathology and atrophy remains unclear. Our goals were twofold: (a) investigate the association between baseline tau-PET patterns and longitudinal atrophy in the AD continuum; (b) characterize heterogeneity as a continuous phenomenon over the conventional notion using discrete subgroups. METHODS: In 366 individuals (amyloid-beta-positive: cognitively normal, prodromal AD, AD dementia; amyloid-beta-negative healthy), we examined the association between tau-PET patterns (operationalized as a continuous phenomenon and a discrete phenomenon) and longitudinal sMRI. RESULTS: We observed a differential association between tau-PET patterns and longitudinal atrophy. Heterogeneity, measured continuously, may offer an alternative characterization, sharing correspondence with the conventional subgrouping. DISCUSSION: Site and the rate of atrophy are modulated differentially by tau-PET patterns in the AD continuum. We postulate that heterogeneity be treated as a continuous phenomenon for greater sensitivity over the current/conventional discrete subgrouping.

scholarly journals Detection of amyloid-beta and tau in tear fluid of patients with Alzheimer’s disease

2020 ◽  
Author(s):  
Marlies Gijs ◽  
Inez H.G.B. Ramakers ◽  
Pieter Jelle Visser ◽  
Frans R.J. Verhey ◽  
Marjo P.H. van de Waarenburg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Tear Fluid ◽  
Subjective Cognitive Decline ◽  
Amyloid Beta Peptides ◽  
Non Invasive ◽  
Beta Peptides ◽  
Dementia Patients ◽  
T Tau

Abstract Background There is growing interest in finding non-invasive alternatives to cerebrospinal fluid (CSF) that could serve as front-line diagnostics for Alzheimer’s disease (AD). In this study, we investigated AD-specific biomarkers in tear fluid.Methods Tear fluid was collected from 25 patients with subjective cognitive decline SCD), 24 patients with mild cognitive impairment (MCI), 11 dementia patients and nine controls. Amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau levels in tear fluid were determined using multiplex immunoassays.Results Tear t-tau levels in dementia, MCI and SCD patients were higher than in HC (p = 0.002, p = 0.002 and p = 0.013, respectively). A negative correlation between AB42 and t-tau was found in both tear fluid and CSF. Levels of tear p-tau were detectable in patients but not in HC.Conclusions This study shows for the first time presence of amyloid-beta peptides (AB38, AB40, AB42), t-tau and p-tau in tear fluid.

scholarly journals Functional Abnormality Associated With Tau Deposition in Alzheimer’s Disease – A Hybrid Positron Emission Tomography/MRI Study

2021 ◽  
Vol 13 ◽  
Author(s):  
Liping Fu ◽  
Zhi Zhou ◽  
Linwen Liu ◽  
Jinming Zhang ◽  
Hengge Xie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Standardized Uptake Value ◽  
Occipital Lobe ◽  
Posterior Cingulate Cortex ◽  
Functional Abnormality ◽  
Individual Level ◽  
Positron Emission ◽  
Mri Scans ◽  
The Individual

Objective: To investigate the characteristics of tau deposition and its impact on functional connectivity (FC) in Alzheimer’s disease (AD).Methods: Hybrid PET/MRI scans with [18F]-THK5317 and neuropsychological assessments were undertaken in 26 participants with AD and 19 healthy controls (HC). The standardized uptake value ratio (SUVR) of [18F]-THK5317 PET imaging was compared between the AD and HC groups. Significant clusters that revealed higher tau deposition in the AD group compared to the HC group were selected as regions of interest (ROI) for FC analysis. We evaluated the difference in the FC between the two groups for each ROI pair. The clinical and radiological characteristics were compared between the AD patients with negative FC and AD patients with positive FC for exploratory analysis.Results: The bilateral inferior lateral temporal lobe, dorsal prefrontal cortex, precuneus, posterior cingulate cortex, hippocampus, and occipital lobe showed significantly higher [18F]-THK5317 accumulation in AD patients. Decreased FC in regions with higher SUVR was observed in AD patients, and the FC strength was negatively correlated with regional SUVR. Patients with a positive FC exhibited older ages, better cognitive performances, and a lower SUVR than patients with a negative FC.Conclusions: An impact of tau deposition was observed on FC at the individual level in AD patients. Our findings suggested that the combination of tau-PET and rs-fMRI might help predict AD progression.

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