In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

Varrone, Andrea; Mattsson, Patrik; Forsberg, Anton; Takano, Akihiro; Nag, Sangram; Gulyás, Balázs; Borg, Jacqueline; Boellaard, Ronald; Al‐Tawil, Nabil; Eriksdotter, Maria; Zimmermann, Till; Schultze-Mosgau, Marcus; Thiele, Andrea; Hoffmann, Anja; Lammertsma, Adriaan A.; Halldin, Christer

doi:10.1007/s00259-013-2359-1

Cited by 75 publications

(47 citation statements)

References 33 publications

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“…Seven ligands were used; 19 studies used PK11195,18–36 two studies used DAA1106,37–38 one study used vincopetine,39 two studies used DED,40–41 two studies used PBR28,42–43 one study used FEDAA110644 and one study used AA 45. Five of these seven ligands (PK11195, DAA1106, vincopetine, PBR28, FEDAA1106) bind the TSPO on activated microglia, one (DED) binds to MAO-B in activated astrocytes and one (AA) images a metabolic by-product of microglial-induced neuroinflammation 45.…”

Section: Resultsmentioning

confidence: 99%

Imaging of neuroinflammation in dementia: a review

Stefaniak

O’Brien

2015

J Neurol Neurosurg Psychiatry

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We are still very limited in management strategies for dementia, and establishing effective disease modifying therapies based on amyloid or tau remains elusive. Neuroinflammation has been increasingly implicated as a pathological mechanism in dementia and demonstration that it is a key event accelerating cognitive or functional decline would inform novel therapeutic approaches, and may aid diagnosis. Much research has therefore been done to develop technology capable of imaging neuroinflammation in vivo. The authors performed a systematic search of the literature and found 28 studies that used in vivo neuroimaging of one or more markers of neuroinflammation on human patients with dementia. The majority of the studies used positron emission tomography (PET) imaging of the TSPO microglial marker and found increased neuroinflammation in at least one neuroanatomical region in dementia patients, most usually Alzheimer's disease, relative to controls, but the published evidence to date does not indicate whether the regional distribution of neuroinflammation differs between dementia types or even whether it is reproducible within a single dementia type between individuals. It is less clear that neuroinflammation is increased relative to controls in mild cognitive impairment than it is for dementia, and therefore it is unclear whether neuroinflammation is part of the pathogenesis in early stages of dementia. Despite its great potential, this review demonstrates that imaging of neuroinflammation has not thus far clearly established brain inflammation as an early pathological event. Further studies are required, including those of different dementia subtypes at early stages, and newer, more sensitive, PET imaging probes need to be developed.

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Section: Resultsmentioning

confidence: 99%

Imaging of neuroinflammation in dementia: a review

Stefaniak

O’Brien

2015

J Neurol Neurosurg Psychiatry

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“…An increase in TSPO expression has been observed during the onset of disease in amytrophic lateral sclerosis (ALS) patients (147). Similarly, brains of subjects with mild cognitive impairment (MCI), who are at an increased risk of developing Alzheimer's disease (AD), or subjects with mild and early forms of AD, exhibit higher ligand binding compared to age-matched controls (148,149) although other studies contradict this observation (150). Widespread glial activation is likewise associated with the pathological process that occurs in Parkinson's disease (PD) and TSPO ligands have shown increased binding profiles in rat models mimicking the early stages the disease (151).…”

Section: Inflammatory Brain Conditionsmentioning

confidence: 87%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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“…In the aim to explore this process in vivo, a number of PET tracers of TSPO were developed in recent years as an alternative to the reference ligand [ 11 C]PK-11195 ). In AD, clinical studies have found no detection (Varrone et al 2013) or increase of TSPO density (Kreisl et al 2013, Schuitemakeret al 2013 (Martin et al 2010;Boutin et al 2013), traumatic brain injury (Wang et al 2014) and epilepsy (Harhausen et al 2013), and has begun to be used in clinical studies (Corcia et al 2012) although no data are to date available in AD. …”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 96%

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

Sérrière

Tauber

Vercouillie

et al. 2015

Neurobiology of Aging

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We studied concomitantly the level of neuroinflammation and β-amyloid (Aβ) load in the APPswePS1dE9 transgenic mouse model of Alzheimer's disease using positron emission tomography. The translocator protein 18 kDa (TSPO) tracer [(18)F]DPA-714 was used to measure neuroinflammation and [(18)F]AV-45 for Aβ load in mice at 6, 9, 12, 15, and 19 months of age. At 19 months, we also analyzed the neuroinflammatory and neuroanatomic status of mice brains. The main affected brain areas were the cortex and hippocampus, with a concomitant progression of neuroinflammation with increased amyloid burden. At 19 months, no increase in TSPO binding was observed in the cerebellum; immunostaining revealed W0-2-positive plaques, indicating that the amyloid deposits seemed not stimulate inflammation. This finding was in agreement with the observed level of microglia and astrocytes staining. Our findings provide a better understanding of the relationships between neuroinflammation and plaque accumulation in the course of the disease in this mouse model. The monitoring of both processes should be of value to validate potential therapeutic approaches.

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In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

Abstract: This study suggests that TSPO imaging with [(18)F]FEDAA1106 does not enable the detection of microglial activation in AD.

Cited by 75 publications

References 33 publications

Imaging of neuroinflammation in dementia: a review

Imaging of neuroinflammation in dementia: a review

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Amyloid load and translocator protein 18 kDa in APPswePS1-dE9 mice: a longitudinal study

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