Molecular Imaging of Neuroinflammation in Neurodegenerative Disease
Understanding neuroinflammation is integral to developing disease mitigation strategies.
The brain continues to be the test bed for molecular imaging. Recent progress in molecular neuroimaging is providing new methods to assess neuroinflammation changes in the brain.
Of all the mechanisms associated with neurodegenerative diseases, neuroinflammation appears to be the common thread. Once better understood, drug therapies that may inhibit disease progression through inflammation modulation can be developed.
Ongoing research across several neurological disease states suggests that molecular imaging of neuroinflammation may soon reach clinical use. Indeed, the European Commission recently green-lighted a project, Imaging of Neuroinflammation in Neurodegenerative Diseases (INMiND), that started on March 1 with the goal of elucidating the role of neuroinflammation in neurodegenerative diseases through imaging. The consortium consists of more than 20 university partners and others from small and medium-sized enterprises from 13 countries. The project is coordinated by Andreas H. Jacobs, MD, of the European Institute for Molecular Imaging at the University of Münster in Germany.
In activated microglial cells, an increase in the expression of peripheral benzodiazepine receptors (PBR) can be found, suggesting PBR as a target for in vivo PET monitoring of neuroinflammation. The isoquinoline carboxamide derivate PK11195, a nonbenzodiazepine ligand that specifically binds to PBR, is used for PBR imaging.
PK11195 is currently the only imaging technique available to assess neuroinflammation in vivo. Initial studies show that microglial activation in patients with Huntington’s disease correlates with disease progression. “But more significantly, the follow-up showed that microglial activation also is evident in pre-symptomatic Huntington’s gene carriers and can be detected up to 15 years before the onset of disease,” says Moeller. “These findings indicate microglial activation is an early event associated with subclinical progression of Huntington’s disease.”
Another group, this one located at Hammersmith Hospital in London, led by David J. Brooks, MD, used PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (Neurology 2003;61(5):686-689).
Anna Bartels, MD, of the department of neurology at University Medical Centre, Groningen, The Netherlands, assessed the use of PK11195 PET to quantify neuroinflammation and asses the ability of COX-2 inhibition to reduce neuroinflammation in Parkinson’s disease patients (Parkinsonism Relat Disord 2010;16(1):57-59).
“From my studies it became clear that current methods are still insufficient for precise quantification of neuroinflammation,” says Bartels, who adds that several new tracers are being investigated in animal models that may help to further elucidate these issues in humans. While improved quantification methods for PK11195 are being pursued, at this time, the reproducibility of PK11195 measurements has not been established. High reproducibility “is, of course, necessary to investigate the effect of treatments,” she says.
“Identifying these common mechanisms can help in the development of common treatments for the neuroinflammatory component of these diseases,” says Stanley I. Rapoport, MD, of the brain physiology and metabolism section at the U.S. National Institute on Aging in Bethesda, Md.
In one type of PET measurement, imaging probes such as PK11195 enter the brain and bind to receptors on activated brain microglia. Microglia when activated by any of a number of agents release cytokines or nitric oxide as part of the inflammatory process, says Rapoport. When microglial cells are activated, they also over-express the 18-kDa translocator protein TSPO.
“A number of radioactive PET ligands are being tested experimentally that bind to TSPO, but as yet an agreement on which one can be used reliably in clinical practice has not been reached,” says Rapoport, who is exploring an alternative PET approach to neuroinflammation imaging, secondary to the release of cytokines and nitric oxide by activated microglia.
Cytokines bind to specific cytokine receptors on astrocytes within the brain, says Rapoport, and these receptors are coupled to the secondary activation of specific phospholipases, such as cytosolic Ca2+-dependent cPLA2 and secretory sPLA2. Activation of these PLA2s lead to increased release of the second messenger, the n-6 polyunsaturated fatty acid, arachidonic acid (AA), from membrane phospholipids.
“High concentrations of AA caused by this process can damage cell membranes directly, be converted to reactive oxygen species or be metabolized via cyclooxygenase, to proinflammatory products such as prostaglandin E2 (PGE2),” Rapoport says.
cPLA2 also can be activated in neurons secondary to the effects of nitric oxide released by the microglia, via neuronal release of glutamate. “Neuroinflammation involving these processes has been demonstrated, based on post-mortem studies and measurements of AA metabolites in cerebrospinal fluid, in a number of progressive human brain diseases, including Alzheimer’s, HIV-1 dementia and bipolar disorder and schizophrenia,” says Rapoport.
Also, animal studies suggest that neuroinflammation contributes to disease progression. “The questions to be addressed here are 1) How we can image neuroinflammation in the early stages of disease and along its time course; 2) The extent to which neuroinflammation is related to cognitive decline and behavioral abnormalities; and 3) Whether we can use the PET AA imaging approach to evaluate therapies that down-regulate AA metabolism that may be effective against neuroinflammation, such as aspirin, NSAIDs and lithium,” Rapoport says.
The biological processes that drive microglial reaction in ALS are complex and appear to have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored and may improve understanding of the processes that cause neuroinflammation.
Molecular imaging using tracer techniques such as PK11195 will be important tools in helping define the role of neuroinflammation and also to identify controls of neuroinflammation as a therapeutic strategy in ALS and other neurodegenerative diseases.
Anti-inflammatory drugs already are being investigated for therapeutic intervention, particularly minocycline and cyclooxygenase-2. These therapies have shown in vivo anti-inflammatory, hence neuroprotective properties, indicating that PBR/TSPO can be an important target for monitoring disease progression, therapy response and optimal drug dosage.
The brain continues to be the test bed for molecular imaging. Recent progress in molecular neuroimaging is providing new methods to assess neuroinflammation changes in the brain.
Of all the mechanisms associated with neurodegenerative diseases, neuroinflammation appears to be the common thread. Once better understood, drug therapies that may inhibit disease progression through inflammation modulation can be developed.
Ongoing research across several neurological disease states suggests that molecular imaging of neuroinflammation may soon reach clinical use. Indeed, the European Commission recently green-lighted a project, Imaging of Neuroinflammation in Neurodegenerative Diseases (INMiND), that started on March 1 with the goal of elucidating the role of neuroinflammation in neurodegenerative diseases through imaging. The consortium consists of more than 20 university partners and others from small and medium-sized enterprises from 13 countries. The project is coordinated by Andreas H. Jacobs, MD, of the European Institute for Molecular Imaging at the University of Münster in Germany.
In Huntington’s disease
Neuroinflammation is increasingly understood to be an integral component in disease progression. Thomas G. Moeller, PhD, an adjunct professor of neurology at the University of Washington in Seattle, is working on the cell biology of microglial cells that are the resident macrophages of the brain and spinal cord and act as the main immune defense in the central nervous system. Microglial cells are activated when the central nervous system is injured or diseased and are thus an indicator of neuroinflammation. How to properly image microglia is an ongoing research focus.In activated microglial cells, an increase in the expression of peripheral benzodiazepine receptors (PBR) can be found, suggesting PBR as a target for in vivo PET monitoring of neuroinflammation. The isoquinoline carboxamide derivate PK11195, a nonbenzodiazepine ligand that specifically binds to PBR, is used for PBR imaging.
PK11195 is currently the only imaging technique available to assess neuroinflammation in vivo. Initial studies show that microglial activation in patients with Huntington’s disease correlates with disease progression. “But more significantly, the follow-up showed that microglial activation also is evident in pre-symptomatic Huntington’s gene carriers and can be detected up to 15 years before the onset of disease,” says Moeller. “These findings indicate microglial activation is an early event associated with subclinical progression of Huntington’s disease.”
Another group, this one located at Hammersmith Hospital in London, led by David J. Brooks, MD, used PK11195 PET to localize in vivo microglial activation in patients with multiple system atrophy (Neurology 2003;61(5):686-689).
In Parkinson’s disease
While increasing evidence has demonstrated that neuroinflammation contributes to neuron death in Parkinson’s disease, the value of PK11195 has been questioned, partly due to the involvement of cyclooxygenase (COX) in neuroinflammation.Anna Bartels, MD, of the department of neurology at University Medical Centre, Groningen, The Netherlands, assessed the use of PK11195 PET to quantify neuroinflammation and asses the ability of COX-2 inhibition to reduce neuroinflammation in Parkinson’s disease patients (Parkinsonism Relat Disord 2010;16(1):57-59).
“From my studies it became clear that current methods are still insufficient for precise quantification of neuroinflammation,” says Bartels, who adds that several new tracers are being investigated in animal models that may help to further elucidate these issues in humans. While improved quantification methods for PK11195 are being pursued, at this time, the reproducibility of PK11195 measurements has not been established. High reproducibility “is, of course, necessary to investigate the effect of treatments,” she says.
In Alzheimer’s disease
Post-mortem evidence indicates that neuroinflammation associated with upregulated brain anchidonic acid metabolism affects progressive psychiatric, viral and neurodegenerative brain disorders, such as Alzheimer’s disease.“Identifying these common mechanisms can help in the development of common treatments for the neuroinflammatory component of these diseases,” says Stanley I. Rapoport, MD, of the brain physiology and metabolism section at the U.S. National Institute on Aging in Bethesda, Md.
In one type of PET measurement, imaging probes such as PK11195 enter the brain and bind to receptors on activated brain microglia. Microglia when activated by any of a number of agents release cytokines or nitric oxide as part of the inflammatory process, says Rapoport. When microglial cells are activated, they also over-express the 18-kDa translocator protein TSPO.
“A number of radioactive PET ligands are being tested experimentally that bind to TSPO, but as yet an agreement on which one can be used reliably in clinical practice has not been reached,” says Rapoport, who is exploring an alternative PET approach to neuroinflammation imaging, secondary to the release of cytokines and nitric oxide by activated microglia.
Cytokines bind to specific cytokine receptors on astrocytes within the brain, says Rapoport, and these receptors are coupled to the secondary activation of specific phospholipases, such as cytosolic Ca2+-dependent cPLA2 and secretory sPLA2. Activation of these PLA2s lead to increased release of the second messenger, the n-6 polyunsaturated fatty acid, arachidonic acid (AA), from membrane phospholipids.
“High concentrations of AA caused by this process can damage cell membranes directly, be converted to reactive oxygen species or be metabolized via cyclooxygenase, to proinflammatory products such as prostaglandin E2 (PGE2),” Rapoport says.
cPLA2 also can be activated in neurons secondary to the effects of nitric oxide released by the microglia, via neuronal release of glutamate. “Neuroinflammation involving these processes has been demonstrated, based on post-mortem studies and measurements of AA metabolites in cerebrospinal fluid, in a number of progressive human brain diseases, including Alzheimer’s, HIV-1 dementia and bipolar disorder and schizophrenia,” says Rapoport.
Also, animal studies suggest that neuroinflammation contributes to disease progression. “The questions to be addressed here are 1) How we can image neuroinflammation in the early stages of disease and along its time course; 2) The extent to which neuroinflammation is related to cognitive decline and behavioral abnormalities; and 3) Whether we can use the PET AA imaging approach to evaluate therapies that down-regulate AA metabolism that may be effective against neuroinflammation, such as aspirin, NSAIDs and lithium,” Rapoport says.
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| 1: ALS is a progressive neurodegenerative disorder in which motoneurons in the spinal cord and brain progressively die, resulting in muscle paralysis and death, usually within two to five years of diagnosis. Source: Graham Watts Laboratories for Research into Motor Neuron Disease, University of College London‚ Institute of Neurology 2: beta-III Tubulin and synapsin I in cerebellar granule cells culture. Source: Urte Neniskyte, PhD student, University of Cambridge neurosciences department |
In ALS
Using the ligand PK11195, microglial activation has been demonstrated in amyotrophic lateral sclerosis (ALS) with PET imaging. In ALS, often called Lou Gehrig’s disease, reactive microglial cells, along with astrocytes, actively contribute to the death of motor neurons, although it is currently not clear whether this change occurs early in disease progression or is a reaction to the disease (Curr Mol Med 2011;11(3):246-254).The biological processes that drive microglial reaction in ALS are complex and appear to have both beneficial and deleterious effects on motor neurons. Therapeutic interventions targeting these cells are being explored and may improve understanding of the processes that cause neuroinflammation.
Molecular imaging using tracer techniques such as PK11195 will be important tools in helping define the role of neuroinflammation and also to identify controls of neuroinflammation as a therapeutic strategy in ALS and other neurodegenerative diseases.
Anti-inflammatory drugs already are being investigated for therapeutic intervention, particularly minocycline and cyclooxygenase-2. These therapies have shown in vivo anti-inflammatory, hence neuroprotective properties, indicating that PBR/TSPO can be an important target for monitoring disease progression, therapy response and optimal drug dosage.