scholarly journals PLASMA BIOMARKER FOR ALZHEIMER’S DISEASE: ARE WE READY NOW FOR CLINICAL PRACTICE AND DRUG TRIALS?

2018 ◽  
pp. 1-2
Author(s):  
A. Nakamura
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Utility ◽  
Large Scale ◽  
Amyloid Β ◽  
Imaging Biomarker ◽  
Validation Dataset ◽  
Data Sets ◽  
Detailed Kinetics

To facilitate disease-modifying clinical trials for Alzheimer’s Disease (AD), a blood-based amyloid-β (Aβ) biomarker, which can accurately detect an early pathological signature of AD at prodromal or preclinical stages, has been strongly desired, because it is simpler, less invasive and less costly compared to PET or lumbar puncture. Despite plasma Aβ biomarkers having been extensively investigated, most studies failed to demonstrate clinical utility (1, 2), and at the end of 2016, there was a rather pessimistic mood that this objective might be impossible to realize (3). However, since the latter half of 2017, the situation appears to have changed dramatically, in that several groups have reported potential clinical utility of plasma Aβ biomarkers using different methodologies (4-7). Especially, immunoprecipitation followed by mass spectrometry (IP-MS) assays have shown promising converging evidence. In 2014, we, the National Center for Geriatrics and Gerontology (NCGG) and Koichi Tanaka Mass Spectrometry Research Laboratory at Shimadzu Corporation (Shimadzu), reported that the plasma ratio of Aβ1-42 to a novel APP669-711 fragment (APP669–711/Aβ 1–42) as determined by IP-MS could discriminate high Aβ (Aβ+) individuals from low Aβ (Aβ-) individuals (classified using PiB-PET) with more than 90% accuracy (n=62) (8). In 2017, the Washington University group analyzed detailed kinetics of plasma Aβs, and reported that Aβ42/Aβ40 as measured by IP-MS could distinguish Aβ+ and Aβ- individuals with 88.7% areas under the curve value (n=41) (5). Then very recently, we, in collaboration with the Australian Imaging, Biomarker and Lifestyle Study of Aging (AIBL), have demonstrated that plasma biomarkers, APP669-711/Aβ1-42, Aβ1-40/Aβ1-42, and their composites (composite biomarker), as generated by improved IP-MS methodology performs very well in larger independent datasets: a discovery dataset (NCGG, n=121) and a validation dataset (AIBL, n=252 which includes n=111 PiB-PET and 141 with other ligands) both of which included individuals with normal cognition, MCI and AD. Particularly, the composite biomarker showed very high AUCs in both datasets (discovery 96.7%, n=121, and validation 94.1%, n=111) with accuracy c.a. 90% when using PiB-PET as standard of truth. The findings of the study were considered to be robust, reproducible and reliable because biomarker performance was validated in a blinded manner using independent data sets (Japan and Australia) and involved an established large-scale multicenter cohort (AIBL).

scholarly journals Comparison of Amyloid β and Tau Spread Models in Alzheimer’s Disease

2018 ◽  
Vol 29 (10) ◽  
pp. 4291-4302 ◽  
Author(s):  
Hang-Rai Kim ◽  
Peter Lee ◽  
Sang Won Seo ◽  
Jee Hoon Roh ◽  
Minyoung Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Scale ◽  
Amyloid Β ◽  
Brain Network ◽  
Amyloid Positron Emission Tomography ◽  
Local Spread ◽  
Positron Emission ◽  
Spread Model ◽  
Graph Theoretical Approach

Abstract Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer’s disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models’ performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.

Validation and Clinical Utility of ELISA Methods for Quantification of Amyloid-β Peptides in Cerebrospinal Fluid Specimens from Alzheimer's Disease Studies

2015 ◽  
Vol 45 (2) ◽  
pp. 527-542 ◽  
Author(s):  
D. Richard Lachno ◽  
Barbara A. Evert ◽  
Kaia Maloney ◽  
Brian A. Willis ◽  
Jayne A. Talbot ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Clinical Utility ◽  
Amyloid Β

scholarly journals Quantitative Measurement of Cerebrospinal Fluid Amyloid-β Species by Mass Spectrometry

2020 ◽  
pp. 1-12
Author(s):  
Yusuke Seino ◽  
Takumi Nakamura ◽  
Tomoo Harada ◽  
Naoko Nakahata ◽  
Takeshi Kawarabayashi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Quantitative Measurement ◽  
Amyloid Β ◽  
High Sensitivity ◽  
Csf Biomarkers ◽  
Strongly Correlated ◽  
Csf Levels

Background: High sensitivity liquid chromatography mass spectrometry (LC-MS/MS) was recently introduced to measure amyloid-β (Aβ) species, allowing for a simultaneous assay that is superior to ELISA, which requires more assay steps with multiple antibodies. Objective: We validated the Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 assay by LC-MS/MS and compared it with ELISA using cerebrospinal fluid (CSF) samples to investigate its feasibility for clinical application. Methods: CSF samples from 120 subjects [8 Alzheimer’s disease (AD) with dementia (ADD), 2 mild cognitive dementia due to Alzheimer’s disease (ADMCI), 14 cognitively unimpaired (CU), and 96 neurological disease subjects] were analyzed. Aβ species were separated using the Shimadzu Nexera X2 system and quantitated using a Qtrap 5500 LC-MS/MS system. Aβ1-40 and Aβ1-42 levels were validated using ELISA. Results: CSF levels in CU were 666±249 pmol/L in Aβ1-38, 2199±725 pmol/L in Aβ1-40, 153.7±79.7 pmol/L in Aβ1-42, and 9.78±4.58 pmol/L in Aβ1-43. The ratio of the amounts of Aβ1-38, Aβ1-40, Aβ1-42, and Aβ1-43 was approximately 68:225:16:1. Linear regression analyses showed correlations among the respective Aβ species. Both Aβ1-40 and Aβ1-42 values were strongly correlated with ELISA measurements. No significant differences were observed in Aβ1-38 or Aβ1-40 levels between AD and CU. Aβ1-42 and Aβ1-43 levels were significantly lower, whereas the Aβ1-38/1-42, Aβ1-38/1-43, and Aβ1-40/Aβ1-43 ratios were significantly higher in AD than in CU. The basic assay profiles of the respective Aβ species were adequate for clinical usage. Conclusion: A quantitative LC-MS/MS assay of CSF Aβ species is as reliable as specific ELISA for clinical evaluation of CSF biomarkers for AD.

scholarly journals Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer’s Disease

2021 ◽  
pp. 1-20
Author(s):  
Satya V.V.N. Kothapalli ◽  
Tammie L. Benzinger ◽  
Andrew J. Aschenbrenner ◽  
Richard J. Perrin ◽  
Charles F. Hildebolt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dark Matter ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Imaging Biomarker ◽  
Control Group ◽  
Histopathological Study ◽  
Preclinical Ad

Background: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as “Dark Matter”, and the other, with relatively preserved neurons, “Viable Tissue”. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection.

scholarly journals Impairments of neural circuit function in Alzheimer's disease

2016 ◽  
Vol 371 (1700) ◽  
pp. 20150429 ◽  
Author(s):  
Marc Aurel Busche ◽  
Arthur Konnerth
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Large Scale ◽  
Neural Circuit ◽  
Essential Feature ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Aβ Oligomers ◽  
The Brain

An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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