Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study

Schuitemaker, Alie; Kropholler, Marc A; Boellaard, Ronald; Flier, Wiesje M. van der; Kloet, Reina W.; Doef, Thalia F. van der; Knol, Dirk L.; Windhorst, Albert D.; Luurtsema, Gert; Barkhof, Frederik; Jonker, Cees; Lammertsma, Adriaan A.; Scheltens, Philip; Berckel, Bart N.M. van

doi:10.1016/j.neurobiolaging.2012.04.021

Cited by 153 publications

(124 citation statements)

References 41 publications

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“…These cells are phenotypically altered, suggestive of being reactive to 13 pathological stimuli. This increased microglial activation in the human brain with probable AD can now be reflected also by non-invasive imaging techniques taking advantage of radiotracers (such as microglial translocator protein (TSPO) ligands) used with positron emission tomography [137,138]. Evidence suggests that brain parenchymal Aβ (especially in monomeric form) is capable of priming and thus aiding the activation of microglia in response to pathological stimuli, which in turn produce and release a number of proinflammatory cytokines and chemokines [131,[139][140][141].…”

Section: Neuroinflammation In Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathwayrelated alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.3

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Section: Neuroinflammation In Alzheimer's Diseasementioning

confidence: 99%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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“…Imaging studies of neuroinflammation in AD subjects mainly using [ 11 C]PK-11195 reported an increase in [ 11 C]PK-11195 binding in various cortical regions (entorhinal, frontal, temporoparietal and cingulate cortices) compared to controls [58,60,61,62,63]. Several other putative TSPO-specific ligands with improved pharmacological properties have been developed in preclinical and human studies, including [ 18 F]PBR06 [64], [ 18 F]PBR28 [65], [ 18 F]DPA-713 [15] and [ 11 C]vinpocetine [49].…”

Section: Neuroinflammation In Ad: In Vivo Quantification With Moleculmentioning

confidence: 99%

Neuroinflammation and β Amyloid Deposition in Alzheimer's Disease: In vivo Quantification with Molecular Imaging

Hommet

Mondon²,

Camus³

et al. 2013

Dement Geriatr Cogn Disord

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Background/Aims: Neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Its relationship with underlying β amyloid deposition remains unclear. In vivo visualization of microglial activation has become possible with the development of molecular imaging ligands when used with positron emission tomography (PET). The translocator protein (TSPO) is upregulated during neuroinflammation. Consequently, targeting TSPO with radiolabeled ligands for PET is an attractive biomarker for neuroinflammation. Methods: A review of the research literature on PET imaging which studied in vivo neuroinflammation in AD subjects and its relationship with amyloid load was performed, including papers published between 2001 and 2012. Results: Six studies were included using either [¹¹C]PK-11195 or another non-TSPO radioligand that binds to the monoaminooxidase B. All the studies evaluated amyloid load with [¹¹C]PIB. Microglial activation and astrocytosis are potentially early phenomena in AD. However, the individual levels of amyloid deposition and microglial activation were not correlated. Conclusion: Noninvasive in vivo molecular imaging to visualize neuroinflammation in AD may contribute to our understanding of the kinetics of neuroinflammation and its relationship to the hallmarks of the disease. Both are important for the development of future therapeutic modalities and for quantifying the efficacy of future disease-modifying treatments.

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“…In addition, some PET studies with [ 11 C](R)PK11195 reported a lack of a significant correlation between TSPO overexpression and cognitive severity. 16,17 In recent years, second-generation TSPO candidate tracers have been developed and tested through preclinical experiments and are now being evaluated in clinical settings. PET studies in AD patients using [ 11 (Table 1).…”

mentioning

confidence: 99%

Depiction of microglial activation in aging and dementia: Positron emission tomography with [¹¹C]DPA713 versus [¹¹C](R)PK11195

Yokokura

Terada

Bunai

et al. 2016

J Cereb Blood Flow Metab

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The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BP ND ) in various brain regions using a first-generation translocator protein (TSPO) tracer [11 C](R)PK11195 and a second-generation tracer [11 C]DPA713. The BP ND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer's disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [ 11 C]DPA713 BP ND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when

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Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study

Cited by 153 publications

References 41 publications

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Neuroinflammation and β Amyloid Deposition in Alzheimer's Disease: In vivo Quantification with Molecular Imaging

Depiction of microglial activation in aging and dementia: Positron emission tomography with [¹¹C]DPA713 versus [¹¹C](R)PK11195

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Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study

Cited by 153 publications

References 41 publications

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Neuroinflammation and β Amyloid Deposition in Alzheimer's Disease: In vivo Quantification with Molecular Imaging

Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195

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Product

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Depiction of microglial activation in aging and dementia: Positron emission tomography with [¹¹C]DPA713 versus [¹¹C](R)PK11195