Amyloid-β Positron Emission Tomography Imaging Probes: A Critical Review

Kepe, Vladimir; Moghbel, Mateen; Långström, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung‐Cheng; Satyamurthy, Nagichettiar; Doudet, Doris J.; Mishani, Eyal; Cohen, Robert M.; Høilund‐Carlsen, Poul Flemming; Alavi, Abass; Barrio, Jorge R.

doi:10.3233/jad-130485

Cited by 75 publications

(78 citation statements)

References 80 publications

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“…In human florbetapir-PET analysis with the ADNI dataset, we have not seen a reduction of Aβ pathology by GRN AD risk variant. This result might be due to the PET tracer possessing a higher affinity for dense-core amyloid plaques, although the full in vivo specificity of the tracer remains to be determined [44]. …”

Section: Discussionmentioning

confidence: 99%

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

et al. 2017

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Progranulin (PGRN) is implicated in Alzheimer’s disease (AD) as well as frontotemporal lobar degeneration. Genetic studies demonstrate an association of the common GRN rs5848 variant that results in reduced PGRN levels with increased risk for AD. However, the mechanisms by which PGRN reduction from the GRN AD risk variant or mutation exacerbates AD pathophysiology remain ill defined. Here, we show that the GRN AD risk variant has no significant effects on florbetapir positron emission tomographic amyloid imaging and cerebrospinal fluid (CSF) Aβ levels, whereas it is associated with increased CSF tau levels in human subjects of the Alzheimer’s disease neuroimaging initiative studies. Consistent with the human data, subsequent analyses using the APPswe/PS1ΔE9 (APP/PS1) mouse model of cerebral amyloidosis show that PGRN deficiency has no exacerbating effects on Aβ pathology. In contrast and unexpectedly, PGRN deficiency significantly reduces diffuse Aβ plaque growth in these APP/PS1 mice. This protective effect is due, at least in part, to enhanced microglial Aβ phagocytosis caused by PGRN deficiency-induced expression of TYROBP network genes (TNG) including an AD risk factor Trem2. PGRN-deficient APP/PS1 mice also exhibit less severe axonal dystrophy and partially improved behavior phenotypes. While PGRN deficiency reduces these amyloidosis-related phenotypes, other neuronal injury mechanisms are increased by loss of PGRN, revealing a multidimensional interaction of GRN with AD. For example, C1q complement deposition at synapses is enhanced in APP/PS1 mice lacking PGRN. Moreover, PGRN deficiency increases tau AT8 and AT180 pathologies in human P301L tau-expressing mice. These human and rodent data suggest that global PGRN reduction induces microglial TNG expression and increases AD risk by exacerbating neuronal injury and tau pathology, rather than by accelerating Aβ pathology.

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Section: Discussionmentioning

confidence: 99%

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

et al. 2017

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“…[4] Furthermore, recent failures of numerous anti-amyloid therapies in the final stages of clinical testing have raised questions about the value and purported specificity of Aβ imaging with the existing PET radiopharmaceuticals. [3] New radiotracers for specific Aβ quantification are desperately needed, not only as early detection diagnostics, but also to enable accurate classification of subjects for clinical trials and to assess therapeutic response. [5]…”

Section: Introductionmentioning

confidence: 99%

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

Liang

Holland

Stephenson

et al. 2015

ACS Chem. Neurosci.

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Fluorine-18 labeled 2-fluoro-8-hydroxyquinoline ([18F]CABS13) is a promising positron emission tomography (PET) radiopharmaceutical based on a metal chelator developed to probe the “metal hypothesis of Alzheimer’s disease”. Herein, a practical radiosynthesis of [18F]CABS13 was achieved by radiofluorination followed by deprotection of an O-benzyloxymethyl group. Automated production and formulation of [18F]CABS13 resulted in 19 ± 5% uncorrected radiochemical yield, relative to starting [18F]fluoride, with ≥95% chemical and radiochemical purities, and high specific activity (>2.5 Ci/μmol) within 80 minutes. Temporal PET neuroimaging studies were carried out in female transgenic B6C3- Tg(APPswe,PSEN1dE9)85Dbo/J (APP/PS1) and age-matched wild-type (WT) B6C3F1/J control mice at 3, 7 and 10 months of age. [18F]CABS13 showed an overall higher uptake and retention of radioactivity in the central nervous system of APP/PS1 mice versus WT mice with increasing age. However, PET/magnetic resonance imaging in normal non-human primates revealed that the tracer had low uptake in the brain and rapid formation of a hydrophilic radiometabolite. Identification of more metabolically stable 18F-hydroxyquinolines that can be readily accessed by the radiochemical strategy presented herein is underway.

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“…Some success has been achieved under the existing milestones. Amyloid beta (Ab) ligands for positron emission tomography (PET) imaging are well developed-three (florbetapir, florbetaben, and flutemetamol) have been approved by the FDA and at least one other is in latestage development [19]. The approved ligands are currently included in clinical trials, although none are yet common in clinical use.…”

Section: Biomarkers Of Disease Progressionmentioning

confidence: 99%

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease

Fargo

Aisen

Albert³

et al. 2014

Alzheimer's & Dementia

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With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

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Amyloid-β Positron Emission Tomography Imaging Probes: A Critical Review

Cited by 75 publications

References 80 publications

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease

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Amyloid-β Positron Emission Tomography Imaging Probes: A Critical Review

Cited by 75 publications

References 80 publications

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network

PET Neuroimaging Studies of [18F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease

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Product

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PET Neuroimaging Studies of [¹⁸F]CABS13 in a Double Transgenic Mouse Model of Alzheimer’s Disease and Nonhuman Primates