Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by 11C-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining 11C-Pittsburgh Compound B and 18F-FDG

Carter, Stephen F.; Schöll, Michael; Almkvist, Ove; Wall, Anders; Engler, Henry; Långström, Bengt; Nordberg, Agneta

doi:10.2967/jnumed.110.087031

Cited by 383 publications

(371 citation statements)

References 42 publications

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“…The majority of the published results show that the binding of [ 11 C]DED is increased in AD patients compared with healthy age-matched controls. Interestingly, it has been reported that the increase may be highest in MCI and prodromal AD indicating that astrogliosis measured by [ 11 C]DED is occurring early in the human AD brain [26,27,29]. Thus, the clinical studies are in line with the results obtained in the APP ArcSwe mice in the present study.…”

Section: Discussionsupporting

confidence: 90%

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Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

et al. 2018

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Purpose: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloidbeta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in the nervous system, respond to neurodegenerative disorders through astrogliosis, i.e., converting to a reactive inflammatory state. The aim of this study was to investigate how in vivo quantification of astrogliosis using positron emission tomography (PET) radioligand deuterium-L-[ 11 C]deprenyl ([ 11 C]DED), binding to enzyme monoamine oxidase-B (MAO-B) which is overexpressed in reactive astrocytes during AD, corresponds to expression of glial fibrillary acidic protein (GFAP) and vimentin, i.e., two well-established markers of astrogliosis, during Aβ pathology progression. Procedures: APP ArcSwe mice (n = 37) and wild-type (WT) control mice (n = 23), 2-16-month old, were used to investigate biomarkers of astrogliosis. The radioligand, [ 11 C]DED, was used as an in vivo marker while GFAP, vimentin, and MAO-B were used to investigate astrogliosis and macrophage-associated lectin (Mac-2) to investigate microglia/macrophage activation by immunohistochemistry of the mouse brain. Aβ and GFAP levels were also measured with ELISA in brain homogenates. Results: The intrabrain levels of aggregated Aβ and reactive astrocytes were found to be elevated in APP ArcSwe compared with WT mice. GFAP and vimentin expression increased with age, i.e., with Aβ pathology, in the APP ArcSwe mice. This was not the case for in vivo marker [ 11 C]DED that showed elevated binding of the same magnitude in APP ArcSwe mice compared with WT mice at both 8 and 16 months. Further, immunohistochemistry indicated that there was limited co-expression of MAO-B and GFAP. Conclusions: MAO-B levels are increased early in Aβ pathology progression, while GFAP and vimentin appear to increase later, most likely as a consequence of abundant Aβ plaque formation. Thus, [ 11 C]DED is a useful PET radioligand for the detection of changes in MAO-B at an early stage of Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-017-1153-z) contains supplementary material, which is available to authorized users.Correspondence to: Stina Syvänen; e-mail: stina.syvanen@pubcare.uu.se AD progression but does not measure the total extent of astrogliosis at advanced stages of Aβ pathology.

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Section: Discussionsupporting

confidence: 90%

“…The enzyme is overexpressed in reactive astrocytes, such as those for example in AD. Several clinical PET studies have thus suggested that [ 11 C]DED can be used as a PET ligand for measuring the MAO-B activity in AD brains as an in vivo marker for early disease progression [25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

et al. 2018

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“…Aβ proteins are usually secreted from neurons into the interstitial fluid and can be eliminated in three different ways: 1) proteolytic degradation; 2) passive efflux; 3) active efflux through BBB. P-gp is responsible for the active efflux of Aβ from the brain, and its decreased expression and/or activity leads to increased Aβ levels in the ISF (Figure 3) [48]. These findings support the hypothesis that a P-gp dysfunction in the BBB could play a pivotal role in AD onset.…”

Section: P-glycoprotein (P-gp)supporting

confidence: 77%

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

Contino¹,

Cantore²,

Leopoldo³

et al. 2013

AAD

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AD is the most common form of dementia among the aging population. The neuropathological alterations of AD are represented by the neurofibrillary tangles and extracellular amyloid plaques formation. These two hallmarks are routinely used as biomarkers for AD diagnosis and can allow the identification of the pathology in a late phase. The urgent need to develop probes for PET analysis that can be used in an early diagnosis of this disorder opened a new scenario in which new biomarkers involved in the first step of AD can be easily detected. Recently, an increasing number of studies indicated as new biomarkers P-gp, TLR4, MIR and free serum copper that are involved in the onset of AD. It has been extensively reported that a P-gp dysfunction in brain can be considered one of the causes of the AD accumulation in brain parenchyma and that the up-regulation of inflammatory gene expression and inflammatory signaling due to MIR and TLR4 modulated the development and the progression of AD.

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“…Astrocytes make rapid responses to numerous varieties of damage and pathological changes through a process referred to as reactive astrogliosis. Evidence of astrogliosis has been documented in early stages of AD (Schipper et al 2006;Owen et al 2009;Carter et al 2012), whereas astrocyte death or atrophy in AD brains from patients and animal models has also been reported (Smale et al 1995;Kobayashi et al 2002Kobayashi et al , 2004. Extensive gliosis is present in the hippocampus of adult APP/PS1 mice .…”

Section: Discussionmentioning

confidence: 98%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Evidence for Astrocytosis in Prodromal Alzheimer Disease Provided by ¹¹C-Deuterium-L-Deprenyl: A Multitracer PET Paradigm Combining ¹¹C-Pittsburgh Compound B and ¹⁸F-FDG

Cited by 383 publications

References 42 publications

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

Astroglial Responses to Amyloid-Beta Progression in a Mouse Model of Alzheimer’s Disease

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

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