Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment

Knezevic, Dunja; Mizrahi, Romina

doi:10.1016/j.pnpbp.2017.05.007

Cited by 79 publications

(58 citation statements)

References 73 publications

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“…The contribution of inflammation should be monitored by measuring biological markers in the blood or—though less convenient—in the CSF, in combination with the profiles of genes encoding inflammatory factors [ 142, 143 ] and analysis of the microbioma. Furthermore, as reviewed by Knezevic & Mizrahi [ 144 ], PET analysis offers the possibility of monitoring microglial activation in the brain of AD and MCI subjects, with a series of ligands.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Alzheimer’s Disease, Oligomers, and Inflammation

Forloni

Balducci

2018

JAD

159

110

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The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer’s disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient’s inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.

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Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Alzheimer’s Disease, Oligomers, and Inflammation

Forloni

Balducci

2018

JAD

159

110

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“…mGlu3 receptor might represent a relevant pharmacological target to develop disease-modifying drugs in AD ( Caraci et al, 2018a ). Although no clear data are available in human AD brains, mGlu3 receptor expression appears reduced in several animal models of AD ( Dewar et al, 1991 ; Cha et al, 2001 ; Durand et al, 2014 ; Knezevic and Mizrahi, 2018 ). When treated with the mGlu2/3 receptor agonist LY379268, astrocytes in vitro reduced neuronal Aβ toxicity through the release of neuroprotective factors such as TGF-β1 ( Caraci et al, 2011 ) and BDNF ( Durand et al, 2017 ).…”

Section: Group II Mglu Receptorsmentioning

confidence: 99%

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Spampinato

Copani

Nicoletti

et al. 2018

Front. Mol. Neurosci.

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Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.

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“…Neuroinflammation is thought to play a role in many neuropsychiatric and neurological conditions [1][2][3][4]; however, its exact contribution remains poorly understood [5][6][7]. This is partially due to limited diagnostic tools to measure inflammation in the central nervous system (CNS) [8].…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

et al. 2019

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Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [ 18 F]JNJ-64413739 has been recently disclosed. Procedures: We evaluated [ 18 F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [ 18 F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446. Results: Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [ 18 F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [ 18 F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels. Conclusions: While further work is needed to study [ 18 F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [ 18 F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.

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Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment

Cited by 79 publications

References 73 publications

Alzheimer’s Disease, Oligomers, and Inflammation

Alzheimer’s Disease, Oligomers, and Inflammation

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

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