scholarly journals Detection of Alzheimer Disease Pathology in Patients Using Biochemical Biomarkers: Prospects and Challenges for Use in Clinical Practice

2019 ◽  
Vol 5 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Leslie M Shaw ◽  
Magdalena Korecka ◽  
Michal Figurski ◽  
Jon Toledo ◽  
David Irwin ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Alzheimer Disease ◽  
Clinical Utility ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Appropriate Use ◽  
Tangle Pathology ◽  
Disease Modifying Agents ◽  
Τ Protein

Abstract Background Thirty-four years ago, amyloid-β 1-42 peptide was identified in amyloid plaques from brain tissue obtained from patients with Alzheimer disease (AD) and Down syndrome. This finding led to development of immunoassays for this marker of amyloid plaque burden in cerebrospinal fluid (CSF) approximately 10 years later. Subsequently, research immunoassays were developed for total τ protein and τ phosphorylated at the threonine 181 position. Subsequent studies documented the clinical utility of these biomarkers of amyloid plaque burden or τ tangle pathology in cohorts of living patients. Content We describe the following: (a) clinical utility of AD biomarkers; (b) measurement challenges, including development of mass spectrometry-based reference methods and automated immunoassays; (c) development of “appropriate use criteria” (AUC) guidelines for safe/appropriate use of CSF testing for diagnosis of AD developed by neurologists, a neuroethicist, and laboratorians; (d) a framework, sponsored by the National Institute of Aging-Alzheimer's Association (NIA-AA), that defines AD on the basis of CSF and imaging methods for detecting amyloid plaque burden, τ tangle pathology, and neurodegeneration. This framework's purpose was investigative but has important implications for future clinical practice; (e) recognition of copathologies in AD patients and challenges for developing methods to detect these in living patients. Summary The field can expect availability of validated research tools for detection of AD pathology that support clinical treatment trials of disease-modifying agents and, ultimately, use in clinical practice. Validated methods are becoming available for CSF testing; emergence of validated methods for AD biomarkers in plasma can be expected in the next few years.

Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models

2009 ◽  
Vol 219 (2) ◽  
pp. 173-181 ◽  
Author(s):  
Sandra Pereson ◽  
Hans Wils ◽  
Gernot Kleinberger ◽  
Eileen McGowan ◽  
Mado Vandewoestyne ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Mouse Models ◽  
Amyloid Plaque ◽  
Dense Core ◽  
Plaque Burden

Proton Stimulation Targeting Plaque Magnetite Reduces Amyloid-β Plaque and Iron Redox Toxicity and Improves Memory in an Alzheimer’s Disease Mouse Model

2021 ◽  
pp. 1-16
Author(s):  
Seung-Jun Seo ◽  
Won-Seok Chang ◽  
Jae-Geun Jeon ◽  
Younshick Choi ◽  
EunHo Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Mouse Brain ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Protein Matrix ◽  
Entrance Dose ◽  
Aβ Fibrils

Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48–87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68–82%) and (94–97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p <  0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery.

Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord

2020 ◽  
Vol 77 (3) ◽  
pp. 1315-1330
Author(s):  
Tak-Ho Chu ◽  
Karen Cummins ◽  
Peter K. Stys
Keyword(s):  
Spinal Cord ◽  
Axonal Injury ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Plaque Burden ◽  
Wild Type ◽  
Plaque Deposition ◽  
5Xfad Mice ◽  
The Impact

Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer’s disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells.

scholarly journals Stereologic measures of beta-amyloid load in postmortem autosomal dominant Alzheimer disease brain validate PiB-PET as a useful biomarker

2019 ◽  
Vol 46 (s2) ◽  
pp. S60-S61
Author(s):  
N Sinha ◽  
A Zhou ◽  
Y Li ◽  
N Joseph-Mathurin ◽  
C Xiong ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Autosomal Dominant ◽  
Amyloid Β ◽  
Standardized Uptake Value ◽  
Beta Amyloid ◽  
Postmortem Brain ◽  
Plaque Burden ◽  
List Type ◽  
Potential Biomarker

In vivo positron emission tomography (PET) using [C11]-labeled Pittsburgh Compound B ([C11]PiB) has previously been shown to detect amyloid-β (Aβ) in late-onset Alzheimer disease (LOAD) brain; however, the sensitivity of this technique for detecting β-amyloidosis in autosomal dominant Alzheimer disease (ADAD) has not been systematically investigated. To validate [C11]PiB PET as a useful biomarker of β-amyloidosis, we measured the cortical and regional standardized uptake value ratios (SUVRs) in 16 ADAD and 15 LOAD cases and compared them with histopathologic measures of β-amyloidosis in postmortem brain. The PiB-PET data were obtained between 40–70 min after bolus injection of ∼15 mCi of [11C]PiB. MRI and PiB-PET images were co-registered and SUVRs were generated for several brain regions. Using Aβ immunohistochemistry (10D5, Eli Lilly), the burden of Aβ plaques was quantified in 16 regions of interest using an area fraction fractionator probe (Stereo Investigator, MicroBrightfield, VT). There were regional variations in Aβ plaque burden with highest densities observed in the neocortical areas and the striatum. On spearman correlations, in vivo PiB-PET correlated with postmortem Aβ plaque burden in both LOAD and ADAD, with strongest correlations seen in neocortical areas. In summary, [C11]PiB-PET has utility as a biomarker in both ADAD and LOAD.LEARNING OBJECTIVESThis presentation will enable the learner to:1.Discuss how PET-PiB beta-amyloid imaging is used as a potential biomarker of Alzheimer disease (AD)2.Correlate postmortem neuropathologic evidence of beta-amyloidosis with PET-PiB data, and learn that PET-PiB is a potentially useful tool to detect beta-amyloidosis in presymptomatic and symptomatic individuals

Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease

2021 ◽  
Author(s):  
Charles D. Chen ◽  
Nelly Joseph-Mathurin ◽  
Namita Sinha ◽  
Aihong Zhou ◽  
Yan Li ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Amyloid Β ◽  
Plaque Burden

scholarly journals Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease

PLoS Medicine ◽  
2007 ◽  
Vol 4 (8) ◽  
pp. e262 ◽  
Author(s):  
Matthew L Hemming ◽  
Michaela Patterson ◽  
Casper Reske-Nielsen ◽  
Ling Lin ◽  
Ole Isacson ◽  
...  
Keyword(s):  
Gene Delivery ◽  
Alzheimer Disease ◽  
Therapeutic Approach ◽  
Ex Vivo ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Novel Therapeutic

scholarly journals Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models.

2021 ◽  
Author(s):  
Aarti Patel ◽  
Ryoichi Kimura ◽  
Wen Fu ◽  
Rania Soudy ◽  
David MacTavish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Plaque Burden ◽  
Amyloid Precursor Protein Gene ◽  
Amyloid Β Peptide ◽  
Class B

Abstract Based upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a Class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris Water Maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

scholarly journals Reduction of Amyloid Burden by Proliferated Homeostatic Microglia in Toxoplasma gondii-Infected Alzheimer’s Disease Model Mice

2021 ◽  
Vol 22 (5) ◽  
pp. 2764
Author(s):  
Ji-Hun Shin ◽  
Young Sang Hwang ◽  
Bong-Kwang Jung ◽  
Seung-Hwan Seo ◽  
Do-Won Ham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Toxoplasma Gondii ◽  
Disease Model ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Plaque Burden ◽  
Microglial Phagocytosis ◽  
Microglial Proliferation ◽  
Toxoplasma Gondii Infection

In this study, we confirmed that the number of resident homeostatic microglia increases during chronic Toxoplasma gondii infection. Given that the progression of Alzheimer’s disease (AD) worsens with the accumulation of amyloid β (Aβ) plaques, which are eliminated through microglial phagocytosis, we hypothesized that T. gondii-induced microglial proliferation would reduce AD progression. Therefore, we investigated the association between microglial proliferation and Aβ plaque burden using brain tissues isolated from 5XFAD AD mice (AD group) and T. gondii-infected AD mice (AD + Toxo group). In the AD + Toxo group, amyloid plaque burden significantly decreased compared with the AD group; conversely, homeostatic microglial proliferation, and number of plaque-associated microglia significantly increased. As most plaque-associated microglia shifted to the disease-associated microglia (DAM) phenotype in both AD and AD + Toxo groups and underwent apoptosis after the lysosomal degradation of phagocytosed Aβ plaques, this indicates that a sustained supply of homeostatic microglia is required for alleviating Aβ plaque burden. Thus, chronic T. gondii infection can induce microglial proliferation in the brains of mice with progressed AD; a sustained supply of homeostatic microglia is a promising prospect for AD treatment.

scholarly journals Genetic Depletion of Amylin/Calcitonin Receptors Improves Memory and Learning in Transgenic Alzheimer’s Disease Mouse Models

2021 ◽  
Author(s):  
Aarti Patel ◽  
Ryoichi Kimura ◽  
Wen Fu ◽  
Rania Soudy ◽  
David MacTavish ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Long Term Potentiation ◽  
Therapeutic Benefit ◽  
Plaque Burden ◽  
Amyloid Precursor Protein Gene ◽  
Amyloid Β Peptide ◽  
Class B

AbstractBased upon its interactions with amyloid β peptide (Aβ), the amylin receptor, a class B G protein-coupled receptor (GPCR), is a potential modulator of Alzheimer’s disease (AD) pathogenesis. However, past pharmacological approaches have failed to resolve whether activation or blockade of this receptor would have greater therapeutic benefit. To address this issue, we generated compound mice expressing a human amyloid precursor protein gene with familial AD mutations in combination with deficiency of amylin receptors produced by hemizygosity for the critical calcitonin receptor subunit of this heterodimeric GPCR. These compound transgenic AD mice demonstrated attenuated responses to human amylin- and Aβ-induced depression of hippocampal long-term potentiation (LTP) in keeping with the genetic depletion of amylin receptors. Both the LTP responses and spatial memory (as measured with Morris water maze) in these mice were improved compared to AD mouse controls and, importantly, a reduction in both the amyloid plaque burden and markers of neuroinflammation was observed. Our data support the notion of further development of antagonists of the amylin receptor as AD-modifying therapies.

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