In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease

Gerhard, Alexander; Pavese, Nicola; Hotton, Gary; Turkheimer, Federico; Es, Meltem; Hammers, Alexander; Eggert, Karla; Oertel, Wolfgang H.; Bánati, Richard B.; Brooks, David J.

doi:10.1016/j.nbd.2005.08.002

Cited by 990 publications

(752 citation statements)

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“…Arterial blood was sampled using an automated system for the first 5 minutes. Manual samples were drawn at 2, 4,6,8,10,15,20,25,30,45, and 60 minutes. All patients were genotyped for the genetic polymorphism of rs6971, which affects binding of TSPO radioligands, including [ 11 C]PBR28, both in vitro and in vivo.…”

Section: Pet Imagingmentioning

confidence: 99%

“…This protein can be viewed as a marker for CNS immune activation, because changes in TSPO levels have been shown to reflect changes in glial cell activity. 19,20 TSPO expression is typically elevated in several acute and chronic CNS disorders involving the immune system [21][22][23][24][25] as well as in animal models of acute inflammation 26 or stroke. 19 With regard to periphery-to-brain interactions, lipopolysaccharide (LPS)-induced acute systemic inflammation is followed by a rapid and transient activation of the brain immune system, as demonstrated using the TSPO radioligand [ 11 C]PBR28 in nonhuman primates 27 and humans.…”

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confidence: 99%

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The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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Objective: Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic-to-brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short-and longterm impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function. Methods: Eight males undergoing prostatectomy under general anesthesia were included. Prior to surgery (baseline), at postoperative days 3 to 4, and after 3 months, patients were examined using [ 11 C]PBR28 brain PET imaging to assess brain immune cell activation. Concurrently, systemic inflammatory biomarkers, ex vivo blood tests on immunoreactivity to lipopolysaccharide (LPS) stimulation, and cognitive function were assessed. Results: Patients showed a global downregulation of gray matter [ 11 C]PBR28 binding of 26 6 26% (mean 6 standard deviation) at 3 to 4 days postoperatively compared to baseline (p 5 0.023), recovering or even increasing after 3 months. LPS-induced release of the proinflammatory marker tumor necrosis factor-a in blood displayed a reduction (41 6 39%) on the 3rd to 4th postoperative day, corresponding to changes in [ 11 C]PBR28 distribution volume. Change in Stroop Color-Word Test performance between postoperative days 3 to 4 and 3 months correlated to change in [ 11 C]PBR28 binding (p 5 0.027). Interpretation: This study translates preclinical data on changes in the brain immune system after surgery to humans, and suggests an interplay between the human brain and the inflammatory response of the peripheral innate immune system. These findings may be related to postsurgical impairments of cognitive function. ANN NEUROL 2017;81:572-582 A growing body of evidence suggests that surgical trauma launches a systemic inflammatory response that ultimately reaches and activates the intrinsic immune system of the brain. [1][2][3][4] Triggered by surgery-induced damage-associated molecular patterns (DAMPs), an array of proinflammatory mediators and activated blood-borne immune cells orchestrate a rapid spread of this systemic response to the central nervous system (CNS), with inflammatory markers detectable in human cerebrospinal fluid (CSF) within 12 hours. [4][5][6][7] In surgical rodent models, this periphery-to-brain pathway seems critically dependent on NF-jB and proinflammatory cytokine signaling (eg, tumor necrosis factor-a [TNF-a]) associated with a shortlasting disruption of blood-brain barrier integrity, 2,3,8 migration of peripheral macrophages into the CNS, and subsequent hippocampal neuronal dysfunction and cognitive impairment. 8 In addition to an acute and transient response, often referred to as a syndrome of sickness behavior including fatigue, anorexia, and fever, surgery-induced immune activation may be associated with prolonged impairments in learning,...

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Section: Pet Imagingmentioning

confidence: 99%

mentioning

confidence: 99%

The immune response of the human brain to abdominal surgery

Forsberg

Červenka

Fagerlund

et al. 2017

Annals of Neurology

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“…In early de novo PD patients, [ 11 C]PK11195 PET binding in the midbrain contralateral to the clinically affected side was significantly increased compared to a group of healthy controls and increased microglial activation was associated with putamen dopaminergic deficits and increased motor symptom severity (Ouchi et al, 2005). Moderate/advanced levodopa-treated PD patients showed widespread increases in [ 11 C]PK11195 binding in the pons, basal ganglia, and frontal and temporal cortical regions, which did not correlate with symptom severity and striatal dopaminergic deficits (Gerhard et al, 2006). Moreover, the levels of microglial activation remained stable over a period of 2 years (Gerhard et al, 2006).…”

Section: Neuroinflammationmentioning

confidence: 98%

Imaging in Parkinson's Disease

Politis

Pagano

Niccolini

2017

International Review of Neurobiology

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Section: Rat Cerebral Cortexmentioning

confidence: 99%

“…Its expression is upregulated in activated microglia [66][67][68] , and the upregulation is well correlated with the state of activation [69][70][71] . 11 C-labeled PK11195 is a specific PET ligand for PBR to image activated microglia in the brain, and has been extensively used for quantitative evaluation of brain infl ammation by PET in a number of neurological disorders, such as stroke [72] , multiple sclerosis [69] , Alzheimer disease [73] , Parkinson disease [74] and Huntington disease [75] .Using [ 11 C]PK11195-PET imaging in rats, we demonstrated that unilateral cortical SD induces neurogenic inflammation in the ipsilateral cerebral hemisphere [14] . The highest [ 11 C]PK11195 radioactivity was seen in the initial area of the cortical SD (KCl-microinjected Yilong Cui, et al Role of cortical spreading depression in the pathophysiology of migraine 817 site), and moderate radioactivity was observed in the ipsilateral surrounding areas, but not in the corresponding contralateral areas.…”

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confidence: 99%

Role of cortical spreading depression in the pathophysiology of migraine

2014

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A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic infl ammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.Keywords: cortical spreading depression; migraine; neurogenic inflammation; PET; trigeminal nociceptive pathway ·Review· IntroductionCortical spreading depression (SD), described first by Leao [1] , is a self-propagating wave of transient neuronal/ glial membrane depolarization that is accompanied by a transient negative shift of the direct current (DC) potential [2] and temporal elevation of cerebral blood flow (CBF) [3,4] throughout the cerebral hemisphere at a rate of 2-5 mm/ min [1, 5,6] . The rate of spreading correlates with the observed spread of the aura of a classical migraine [7] , which is characterized by a spot of fl ickering light that appears near the center of the visual field and then gradually expands outward [8][9][10] . Recently, cortical SD has been hypothesized to be the initial event involved in migraine headaches.Moskowitz et al. [11,12] proposed that pro-inflammatory peptides, such as substance P and calcitonin generelated peptide (CGRP), released from trigeminocervical nerve terminals in response to some unknown stimulation, probably cortical SD, induces vasodilation and plasma protein extravasation. Such neurogenic inflammation is thought to trigger a headache via stimulation of trigeminal afferents. Consistent with this hypothesis, cortical SD induced intracranial neurogenic inflammation around the meningeal blood vessels [13][14][15] , and subsequent activation of both peripheral [16] and central [17] trigeminal nociceptive pathways has been described. Here, we review the experimental evidence mainly from neurophysiological studies that has advanced the understanding of whether and how the neurovascular phenomenon of cortical SD causes intracranial neurogenic inflammation, and subsequently participates in triggering a migraine headache. Migraine PathophysiologyA migraine is a recurring neurological disorder characterized Yilong Cui, et al . Role of cortical spreading depression in the pathophysiology of migraine 813 by unilateral, intense, and pulsatile headaches lasting 4-72 h [18] , a...

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In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease

Cited by 990 publications

References 40 publications

The immune response of the human brain to abdominal surgery

The immune response of the human brain to abdominal surgery

Imaging in Parkinson's Disease

Role of cortical spreading depression in the pathophysiology of migraine

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