scholarly journals Functional Neurophysiological Biomarkers of Early-Stage Alzheimer’s Disease: A Perspective of Network Hyperexcitability in Disease Progression

2021 ◽  
pp. 1-28
Author(s):  
Sean Tok ◽  
Abdallah Ahnaou ◽  
Wilhelmus Drinkenburg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Early Stage ◽  
Imaging Techniques ◽  
Disease Mechanism ◽  
Erroneous Conclusion ◽  
Disease Trajectory ◽  
Potential Biomarker ◽  
Lines Of Evidence

Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological biomarker of Alzheimer’s disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential biomarker of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this indication. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD.

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

P1-066: Amyloid β oligomers as a potential biomarker for early-stage Alzheimer's disease

2011 ◽  
Vol 7 ◽  
pp. S131-S131
Author(s):  
Kim Bruggink ◽  
H. Bea Kuiperij ◽  
Marcel M. Verbeek
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Amyloid Β ◽  
Potential Biomarker

P4-039: CSF tau protein phosphorylated at threonine 231 as a potential biomarker of early-stage Alzheimer's disease

2013 ◽  
Vol 9 ◽  
pp. P717-P717
Author(s):  
Mirjana Babic ◽  
Ivana Kustek ◽  
Natasa Klepac ◽  
Fran Borovecki ◽  
Patrick Hof ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Early Stage ◽  
Potential Biomarker

Advent of Proteomic Tools for Diagnostic Biomarker Analysis in Alzheimer’s Disease

2020 ◽  
Vol 21 (10) ◽  
pp. 965-977
Author(s):  
Manisha Singh ◽  
Surinder P. Singh ◽  
P.K. Dubey ◽  
R Rachana ◽  
Shalini Mani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Diagnostic Tools ◽  
Disease Etiology ◽  
Detection Model ◽  
Therapeutic Trials ◽  
Biomarker Analysis

: Locating remedies for Alzheimer’s disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated- Tau (pTau) 181 and Amyloid-β (Aβ) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD.

scholarly journals sTREM 2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers

2016 ◽  
Vol 8 (5) ◽  
pp. 466-476 ◽  
Author(s):  
Marc Suárez‐Calvet ◽  
Gernot Kleinberger ◽  
Miguel Ángel Araque Caballero ◽  
Matthias Brendel ◽  
Axel Rominger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Early Stage ◽  
Neuronal Injury ◽  
Cerebrospinal Fluid Levels ◽  
Potential Biomarker ◽  
Fluid Levels

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.

Recognition Memory for the Infrequent in Young, Old, and Early Stage Alzheimer's Disease: Evidence for Two Types of Familiarity

2000 ◽  
Author(s):  
David A. Balota ◽  
Gregory C. Burgess ◽  
Michael J. Cortese ◽  
David R. Adams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Recognition Memory ◽  
Early Stage ◽  
Young Old

Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

2019 ◽  
Vol 16 (11) ◽  
pp. 1007-1017 ◽  
Author(s):  
James G. McLarnon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Chronic Inflammation ◽  
Preventive Strategy ◽  
Subsequent Work ◽  
Activated Microglia ◽  
Starting Point ◽  
Anti Inflammatory ◽  
Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

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