Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

2021 ◽  
pp. 1-14
Author(s):  
Andrew L. Zhou ◽  
Nidhi Sharda ◽  
Vidur V. Sarma ◽  
Kristen M. Ahlschwede ◽  
Geoffry L. Curran ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Single Photon ◽  
Photon Emission ◽  
Amyloid Β ◽  
Emission Computed Tomography ◽  
Systemic Injection ◽  
Age Related ◽  
Age Dependent ◽  
Plasma Pharmacokinetics ◽  
The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

scholarly journals Magnetic Resonace–Based Attenuation Correction for Micro–Single-Photon Emission Computed Tomography

2012 ◽  
Vol 11 (2) ◽  
pp. 7290.2011.00036 ◽  
Author(s):  
Vincent Keereman ◽  
Yves Fierens ◽  
Christian Vanhove ◽  
Tony Lahoutte ◽  
Stefaan Vandenberghe
Keyword(s):  
Attenuation Correction ◽  
Single Photon ◽  
Photon Emission ◽  
The Body ◽  
Emission Computed Tomography ◽  
Micro Ct ◽  
Mr Images ◽  
Brain Scans ◽  
The Brain ◽  
Photon Emission Computed Tomography

Attenuation correction is necessary for quantification in micro–single-photon emission computed tomography (micro-SPECT). In general, this is done based on micro–computed tomographic (micro-CT) images. Derivation of the attenuation map from magnetic resonance (MR) images is difficult because bone and lung are invisible in conventional MR images and hence indistinguishable from air. An ultrashort echo time (UTE) sequence yields signal in bone and lungs. Micro-SPECT, micro-CT, and MR images of 18 rats were acquired. Different tracers were used: hexamethylpropyleneamine oxime (brain), dimercaptosuccinic acid (kidney), colloids (liver and spleen), and macroaggregated albumin (lung). The micro-SPECT images were reconstructed without attenuation correction, with micro-CT-based attenuation maps, and with three MR-based attenuation maps: uniform, non-UTE-MR based (air, soft tissue), and UTE-MR based (air, lung, soft tissue, bone). The average difference with the micro-CT-based reconstruction was calculated. The UTE-MR-based attenuation correction performed best, with average errors ≤ 8% in the brain scans and ≤ 3% in the body scans. It yields nonsignificant differences for the body scans. The uniform map yields errors of ≤ 6% in the body scans. No attenuation correction yields errors ≥ 15% in the brain scans and ≥ 25% in the body scans. Attenuation correction should always be performed for quantification. The feasibility of MR-based attenuation correction was shown. When accurate quantification is necessary, a UTE-MR-based attenuation correction should be used.

Single Photon Emission Computed Tomography of the Brain in Patients with Chemical Sensitivities

1994 ◽  
Vol 10 (4-5) ◽  
pp. 573-577
Author(s):  
Theodore R. Simon ◽  
David C. Hickey ◽  
Cynthia E. Fincher ◽  
Alfred R. Johnson ◽  
Gerald H. Ross ◽  
...  
Keyword(s):  
Psychological Symptoms ◽  
Single Photon ◽  
Single Case ◽  
Photon Emission ◽  
Clinical Syndrome ◽  
Emission Computed Tomography ◽  
Desert Storm ◽  
Petroleum Distillates ◽  
Other Substances ◽  
The Brain

Chemical sensitivities display a recurrent pattern on scintigraphic examinations of the brain. The pattern can include mismatching between early and late imaging, multiple hot and cold foci distributed throughout the cortex without regard to lobar distribution (salt and pepper pattern), temporal asymmetries, and sometimes increased activity in the basal ganglia. This study used Desert Shield/Desert Storm veterans who present with abnormal neurological and psychological symptoms as a model to exhibit abnormalities by brain scintigraphy. These are typical of those seen in patients with documented exposure to neurotoxic compounds who develop a clinical syndrome that has been termed chemical sensitivity. Exposure to cocaine, alcohol, and other substances of abuse can result in abnormal scintigrams of the brain using tracers such as [technetium 99m]hexamethylpropyleneoxime. This study used techniques combining regional cerebral blood flow data with delayed distributional data after the intracellular conversion of the tracer into a hydrophilic molecule. In addition to delayed image abnormalities, a mismatch occurs in the regional activity between the two image sets of the veterans. This degree of mismatch was not seen in control subjects who were screened for avoidance of neurotoxic agents. Patterns identified from examinations performed on patients with known exposure to petroleum distillates, pesticides and other materials linked with neurotoxicity were identified in some veterans of the Desert Shield/Desert Storm operation. A single case of repeated examinations on a veteran showed a reversion of these patterns toward normal after therapy. This reversion followed independent assessments of clinical improvement.

scholarly journals Imaging Amyloid-β Deposits In Vivo

2002 ◽  
Vol 22 (9) ◽  
pp. 1035-1041 ◽  
Author(s):  
Brian J. Bacskai ◽  
William E. Klunk ◽  
Chester A. Mathis ◽  
Bradley T. Hyman
Keyword(s):  
Single Photon ◽  
Senile Plaques ◽  
Photon Emission ◽  
Multiphoton Microscopy ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
High Sensitivity ◽  
Emission Computed Tomography ◽  
Tissue Samples

Alzheimer disease (AD) is an illness that can only be diagnosed with certainty with postmortem examination of brain tissue. Tissue samples from afflicted patients show neuronal loss, neurofibrillary tangles (NFTs), and amyloid-β plaques. An imaging technique that permitted in vivo detection of NFTs or amyloid-β plaques would be extremely valuable. For example, chronic imaging of senile plaques would provide a readout of the efficacy of experimental therapeutics aimed at removing these neuropathologic lesions. This review discusses the available techniques for imaging amyloid-β deposits in the intact brain, including magnetic resonance imaging, positron emission tomography, single photon emission computed tomography, and multiphoton microscopy. A variety of agents that target amyloid-β deposits specifically have been developed using one or several of these imaging modalities. The difficulty in developing these tools lies in the need for the agents to cross the blood-brain barrier while recognizing amyloid-β with high sensitivity and specificity. This review describes the progress in developing reagents suitable for in vivo imaging of senile plaques.

scholarly journals SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Tobias Gustavsson ◽  
Stina Syvänen ◽  
Paul O’Callaghan ◽  
Dag Sehlin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ex Vivo ◽  
Photon Emission ◽  
Amyloid Β ◽  
Emission Computed Tomography ◽  
Brain Uptake ◽  
Brain Distribution ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

Abstract Background Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants – RmAb158, the recombinant murine version of BAN2401, which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients, and the bispecific RmAb158-scFv8D3, which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis. Methods A single intravenous injection of iodine-125 (125I)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice (tg-ArcSwe). In vivo single-photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks. Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβ and CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with Aβ. Results Despite faster blood clearance, [125I]RmAb158-scFv8D3 displayed higher brain exposure than [125I]RmAb158 throughout the study. The brain distribution of [125I]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology, while [125I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times. Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for [125I]RmAb158-scFv8D3, whereas [125I]RmAb158 displayed retention and Aβ interactions in lateral ventricles. Conclusions The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging. Moreover, it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

Neuroimaging in dementia and depression

2000 ◽  
Vol 6 (2) ◽  
pp. 109-119 ◽  
Author(s):  
John O'Brien ◽  
Bob Barber
Keyword(s):  
Computed Tomography ◽  
Brain Mapping ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Positron Emission ◽  
Magnetic Resonance Imaging Mri ◽  
Near Future ◽  
The Brain ◽  
Photon Emission Computed Tomography

Neuroimaging is traditionally divided into structural and functional imaging. Structural imaging looks at brain structure or anatomy and includes computed tomography (CT) and magnetic resonance imaging (MRI). Functional techniques seek to examine the physiological functioning of the brain, either at rest or during activation, and include single photon emission computed tomography (SPECT), positron emission tomography (PET), MRI spectroscopy, functional MRI (fMRI) and encephalographic brain mapping. Although fMRI, MRI spectroscopy and brain mapping are likely to have clinical applications in the near future, the main imaging modalities of current clinical relevance to psychiatrists are CT, MRI and SPECT, which will be the focus of this article.

scholarly journals Advances in the Management of Cerebral Vascular Disease

2015 ◽  
Vol 1 (2) ◽  
pp. 86
Author(s):  
Muhammad Imran Qadir ◽  
Hina Kanwal
Keyword(s):  
Vascular Disease ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Industrialized Countries ◽  
Cerebral Vascular Disease ◽  
Neurologic Disability ◽  
The Brain ◽  
Photon Emission Computed Tomography ◽  
Cerebral Vascular

A cerebral vascular disease occurred with the arteries of brain due to the less supply of blood.  Stroke is mostly caused by cerebral vascular disease and it is also a common cause of vascular dementia due to reduced oxygen supply and blood flow to the brain. In industrialized countries, neurologic disability is most frequently caused by cerebeovascular disease. Individuals with cardiovascular disease, diabetes and high blood pressure etc are at higher possibility for cerebral vascular disease. After malignancy and heart disease, cerebral vascular disease is the third leading of death and estimated that an average 500,000 new stroke occurred in each year. Advance techniques such as Carotid Endarterectomy, Magnetic resonance imaging, Angiography and Single photon emission computed tomography etc are used for management of cerebral vascular disease.

Neuroimaging technologies

2020 ◽  
pp. 101-112
Author(s):  
Mark Woolrich ◽  
Mark Jenkinson ◽  
Clare Mackay
Keyword(s):  
Brain Imaging ◽  
Single Photon ◽  
Photon Emission ◽  
Experimental Medicine ◽  
Emission Computed Tomography ◽  
Positron Emission ◽  
Brain Structure And Function ◽  
Magnetic Resonance Imaging Mri ◽  
And Function ◽  
The Brain

The brain is a highly complex system that is inaccessible to biopsy, which puts human brain imaging at the heart of our attempts to understand psychiatric disorders. Imaging has the potential to uncover the pathophysiology, provide biomarkers for use in the development and monitoring of treatments, and stratify patients for studies and trials. This chapter introduces the three main brain imaging technologies that are used to assay brain structure and function: magnetic resonance imaging (MRI), molecular imaging positron emission tomography (PET), and single-photon emission computed tomography (SPECT); electrophysiology [electroencephoaography (EEG)]; and magnetoencephalograpy (MEG). The chapter outlines the principles behind their use and the nature of the information that can be extracted. Together, these brain imaging methods can provide complementary windows into the living brain as an increasingly essential suite of tools for experimental medicine in psychiatry.

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