scholarly journals Network-level permutation entropy of resting-state MEG recordings: a novel biomarker for early-stage Alzheimer’s disease?

2021 ◽  
pp. 1-44
Author(s):  
Elliz P. Scheijbeler ◽  
Anne M. van Nifterick ◽  
Cornelis J. Stam ◽  
Arjan Hillebrand ◽  
Alida A. Gouw ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Resting State ◽  
Early Stage ◽  
Brain Regions ◽  
Permutation Entropy ◽  
Subjective Cognitive Decline ◽  
Local Activity ◽  
Theta Power ◽  
Potential Biomarker

Abstract Objective. Increasing evidence suggests that measures of signal variability and complexity could present promising biomarkers for Alzheimer’s disease (AD). Earlier studies have however been limited to the characterization of local activity. Here, we investigate whether a network version of permutation entropy could serve as a novel biomarker for early-stage AD. Methods. Resting-state source-space magnetoencephalography was recorded in 18 subjects with subjective cognitive decline (‘SCD’) and 18 subjects with mild cognitive impairment (‘MCI’). Local activity was characterized by permutation entropy (PE). Network interactions were studied using the inverted Joint Permutation Entropy (JPEinv), corrected for volume conduction. Results. The JPEinv showed a reduction of nonlinear connectivity in MCI subjects in the theta and alpha band. Local PE showed increased theta-band entropy. Between-group differences were widespread across brain regions. ROC analysis of classification of MCI versus SCD subjects revealed that a linear regression model trained on JPEinv features (78.4% [62.5–93.3%]) slightly outperformed PE (76.9% [60.3–93.4%]) and relative theta power based models (76.9% [60.4–93.3%]). Conclusion. Classification performance of theta JPEinv was at least as good as the relative theta power benchmark. The JPEinv is therefore a potential biomarker for early-stage AD, and should be explored in larger studies.

scholarly journals Resting-state functional reorganisation in Alzheimer’s disease and amnestic mild cognitive impairment: protocol for a systematic review and meta-analysis

BMJ Open ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. e049798
Author(s):  
Diyang Lyu ◽  
Taoran Li ◽  
Xuanxin Lyu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Decline ◽  
Resting State ◽  
Assessment Tool ◽  
Brain Regions ◽  
Amnestic Mild Cognitive Impairment ◽  
Subjective Cognitive Decline

IntroductionThe incidence of Alzheimer’s disease (AD) is increasing rapidly, causing a growing burden to health and economic worldwide. Several clinical trials in the past decade failed to find solutions, and there remains a lack of an effective treatment. The evidence suggests that early intervention for neurodegeneration would likely be effective in preventing cognitive decline. Cognitive decline in AD occurs continuously over a long period; however, there remains a lack of simple, rapid and accurate approach for diagnosis of amnestic mild cognitive impairment or subjective cognitive decline due to underlying Alzheimer’s pathology. Resting-state functional MRI (rs-fMRI) determines the functional activities of the human brain non-invasively. The amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) are rs-fMRI indicators with high repeatability. They have been studied as early diagnostic imaging markers for other diseases and may be promising markers also for AD.Methods and analysisThe following electronic literature databases will be searched from inception to December 2021: Medline-Ovid, Medline-PubMed, EMBase-Ovid, Cochrane Central and ClinicalTrials.gov. Two independent reviewers will select studies with eligible criteria, extract data and assess the quality of the original studies with our quality assessment tool individually. Missing data will be requested by sending emails to the corresponding authors. Brain regions will be presented for ALFF/fALFF and ReHo by performing activation likelihood estimation with the Seed-based d Mapping-Permutation of subject images V.6.21 software. Meta-regression will be performed to determine the potential brain regions that may strongly correlate with cognitive decline progression. Subgroup analysis, funnel plot, Egger’s test and sensitivity analysis will be conducted to detect and explain potential heterogeneity.Ethics and disseminationThis study does not require formal ethical approval. The findings will be submitted to a peer-review journal.PROSPERO registration numberCRD42021229009.

scholarly journals Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Hu ◽  
Lan Tan ◽  
Yan-Lin Bi ◽  
Wei Xu ◽  
Lin Tan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Peripheral Blood ◽  
Late Onset ◽  
Early Stage ◽  
Susceptibility Gene ◽  
Subjective Cognitive Decline ◽  
Preclinical Ad ◽  
T Tau ◽  
New Evidence

AbstractThe bridging integrator 1 (BIN1) gene is the second most important susceptibility gene for late-onset Alzheimer’s disease (LOAD) after apolipoprotein E (APOE) gene. To explore whether the BIN1 methylation in peripheral blood changed in the early stage of LOAD, we included 814 participants (484 cognitively normal participants [CN] and 330 participants with subjective cognitive decline [SCD]) from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Then we tested associations of methylation of BIN1 promoter in peripheral blood with the susceptibility for preclinical AD or early changes of cerebrospinal fluid (CSF) AD-related biomarkers. Results showed that SCD participants with significant AD biological characteristics had lower methylation levels of BIN1 promoter, even after correcting for covariates. Hypomethylation of BIN1 promoter were associated with decreased CSF Aβ42 (p = 0.0008), as well as increased p-tau/Aβ42 (p = 0.0001) and t-tau/Aβ42 (p < 0.0001) in total participants. Subgroup analysis showed that the above associations only remained in the SCD subgroup. In addition, hypomethylation of BIN1 promoter was also accompanied by increased CSF p-tau (p = 0.0028) and t-tau (p = 0.0130) in the SCD subgroup, which was independent of CSF Aβ42. Finally, above associations were still significant after correcting single nucleotide polymorphic sites (SNPs) and interaction of APOE ɛ4 status. Our study is the first to find a robust association between hypomethylation of BIN1 promoter in peripheral blood and preclinical AD. This provides new evidence for the involvement of BIN1 in AD, and may contribute to the discovery of new therapeutic targets for AD.

scholarly journals RNA and Oxidative Stress in Alzheimer’s Disease: Focus on microRNAs

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Akihiko Nunomura ◽  
George Perry
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Early Stage ◽  
Brain Regions ◽  
Prodromal Stage ◽  
Adaptive Mechanisms ◽  
Therapeutic Tools ◽  
Key Events

Oxidative stress (OS) is one of the major pathomechanisms of Alzheimer’s disease (AD), which is closely associated with other key events in neurodegeneration such as mitochondrial dysfunction, inflammation, metal dysregulation, and protein misfolding. Oxidized RNAs are identified in brains of AD patients at the prodromal stage. Indeed, oxidized mRNA, rRNA, and tRNA lead to retarded or aberrant protein synthesis. OS interferes with not only these translational machineries but also regulatory mechanisms of noncoding RNAs, especially microRNAs (miRNAs). MiRNAs can be oxidized, which causes misrecognizing target mRNAs. Moreover, OS affects the expression of multiple miRNAs, and conversely, miRNAs regulate many genes involved in the OS response. Intriguingly, several miRNAs embedded in upstream regulators or downstream targets of OS are involved also in neurodegenerative pathways in AD. Specifically, seven upregulated miRNAs (miR-125b, miR-146a, miR-200c, miR-26b, miR-30e, miR-34a, miR-34c) and three downregulated miRNAs (miR-107, miR-210, miR-485), all of which are associated with OS, are found in vulnerable brain regions of AD at the prodromal stage. Growing evidence suggests that altered miRNAs may serve as targets for developing diagnostic or therapeutic tools for early-stage AD. Focusing on a neuroprotective transcriptional repressor, REST, and the concept of hormesis that are relevant to the OS response may provide clues to help us understand the role of the miRNA system in cellular and organismal adaptive mechanisms to OS.

scholarly journals Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shan-Shan Wang ◽  
Zi-Kai Liu ◽  
Jing-Jing Liu ◽  
Qing Cheng ◽  
Yan-Xia Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Disease Stage ◽  
Assay Method ◽  
Imaging Probe ◽  
Asparaginyl Endopeptidase ◽  
Potential Biomarker ◽  
The Brain

Abstract Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

scholarly journals Platelet phosphorylated TDP-43: An exploratory study for a peripheral surrogate biomarker development for Alzheimer’s disease

2017 ◽  
Author(s):  
Rodger Wilhite ◽  
Jessica Sage ◽  
Abdurrahman Bouzid ◽  
Tyler Primavera ◽  
Abdulbaki Agbas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Clinical Signs ◽  
Brain Regions ◽  
Post Mortem ◽  
Disease Prognosis ◽  
Post Mortem Brain ◽  
And Control ◽  
Lateral Sclerosis

AbstractAim: Alzheimer’s disease (AD) and other forms of dementia create a non-curable disease population in World’s societies. To develop a blood-based biomarker is important so that the remedial or disease-altering therapeutic intervention for AD patients would be available at the early stage. Materials & Methods: TDP-43 levels were analyzed in post-mortem brain tissue and platelets of AD and control subjects. Results: We observed an increased TDP-43 (<60%) in post-mortem AD brain regions and similar trends were also observed in patient’s platelets. Conclusion: Platelet TDP-43 could be used as a surrogate biomarker that is measurable, reproducible, and sensitive for screening the patients with some early clinical signs of AD and can be used to monitor disease prognosis.Lay abstractIn this study, we explore to identify an Alzheimer’s disease-selective phospho-specific antibody that recognizes the diseased form of TDP-43 protein in patient’s blood-derived platelets. Our results suggest that selective anti-phosphorylated TDP-43 antibody discriminates Alzheimer’s disease from non-demented controls and patients with amyotrophic lateral sclerosis. Therefore, platelet screening with a selective antibody could potentially be a useful tool for diagnostic purposes for Alzheimer’s disease.

scholarly journals Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow Is Linked to Alzheimer's Pathology

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 637-638
Author(s):  
Feng Han ◽  
Jing Chen ◽  
Aaron Belkin-Rosen ◽  
Yameng Gu ◽  
Liying Luo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Resting State ◽  
Early Stage ◽  
Adult Population ◽  
Critical Role ◽  
Low Frequency ◽  
Amyloid Β ◽  
Blood Oxygenation

Abstract Alzheimer’s disease (AD) is the most common cause of dementia in the old adult population. AD pathogenesis has been linked to the aggregation of toxic proteins, e.g., amyloid-β and tau. The glymphatic system may play an important role in clearing out these proteins via cerebrospinal fluid (CSF) flows through perivascular and interstitial spaces. Recent studies have suggested low-frequency (&lt;0.1 Hz), sleep-dependent global blood-oxygenation-dependent-level (gBOLD; global resting-state functional MRI signal) during resting state is coupled with CSF movements, suggesting their potential link to glymphatic function. Here, we directly investigated whether the coupling between the gBOLD and CSF signals is related to AD-related pathology. By analyzing neuroimaging, neurobiological, and neuropsychological data from 118 human subjects (58-90 years of age; AD, early-stage AD, and control subjects included) collected in the Alzheimer's Disease Neuroimaging Initiative project, we found a strong coupling between the gBOLD and CSF signals. More importantly, the strength of this gBOLD-CSF coupling was significantly correlated with cortical amyloid-β level (p = 0.019), cognitive decline in the subsequent two years (p = 0.013), disease severity (p = 0.035), and several AD-related risk factors, including aging (p = 0.011), and gender (p = 0.026). These findings provide initial evidence for the critical role of resting-state low-frequency (&lt;0.1 Hz) neural/physiological dynamics in AD pathology. They also suggest that the gBOLD-CSF coupling may serve as a non-invasive imaging marker for gauging the glymphatic function.

scholarly journals A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Ebru Ercan-Herbst ◽  
Jens Ehrig ◽  
David C. Schöndorf ◽  
Annika Behrendt ◽  
Bernd Klaus ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Temporal Cortex ◽  
Brain Regions ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Small Set ◽  
Human Brains

AbstractTau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer’s disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking. Here we apply a comprehensive electrochemiluminescence ELISA assay to analyze twenty-five different PTM sites as well as tau oligomerization in control and sporadic AD brain. The samples were classified as Braak stages 0–I, II or III–IV, corresponding to the progression of microscopically detectable tau pathology throughout different brain regions. We found that soluble tau multimers are strongly increased at Braak stages III–IV in all brain regions under investigation, including the temporal cortex, which does not contain NFTs or misfolded oligomers at this stage of pathology. We additionally identified five phosphorylation sites that are specifically and consistently increased across the entorhinal cortex, hippocampus and temporal cortex in the same donors. Three of these sites correlate with tau multimerization in all three brain regions, but do not overlap with the epitopes of phospho-sensitive antibodies commonly used for the immunohistochemical detection of NFTs. Our results thus suggest that soluble multimers are characterized by a small set of specific phosphorylation events that differ from those dominating in mature NFTs. These findings shed light on early PTM changes of tau during AD pathogenesis in human brains.

P1-273: Neuronal Activity Derived From Resting State Functional MRI: A Potential Biomarker for Alzheimer's Disease

2016 ◽  
Vol 12 ◽  
pp. P521-P521
Author(s):  
Samaneh Kazemifar ◽  
Kathryn Manning ◽  
Nagalingam Rajakumar ◽  
Francisco A. Gómez ◽  
Andrea Soddu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Mri ◽  
Neuronal Activity ◽  
Resting State ◽  
Potential Biomarker

Quantitative Study of the Changes in Cerebral Blood Flow and Iron Deposition During Progression of Alzheimer’s Disease

2020 ◽  
Vol 78 (1) ◽  
pp. 439-452
Author(s):  
Dongxue Li ◽  
Yuancheng Liu ◽  
Xianchun Zeng ◽  
Zhenliang Xiong ◽  
Yuanrong Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Early Diagnosis ◽  
Time Window ◽  
Brain Regions ◽  
Iron Deposition ◽  
Imaging Biomarker ◽  
Subjective Cognitive Decline

Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p < 0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD.

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