An in vivo <sup>11</sup>C‐<scp>PK PET</scp> study of microglia activation in Fatal Familial Insomnia

Iaccarino, Leonardo; Presotto, Luca; Bettinardi, Valentino; Roiter, Ignazio; Capellari, Sabina; Parchi, Piero; Cortelli, Pietro; Perani, Daniela

doi:10.1002/acn3.498

Cited by 10 publications

(5 citation statements)

References 48 publications

(147 reference statements)

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“…The six SYM‐carriers underwent an in‐depth neurological evaluation, including the ALS Functional Rating Scale‐Revised (ALSFRS‐r) for the assessment of severity of ALS and neuropsychological evaluation to evaluate cognitive efficiency. Ten healthy controls were included for statistical comparison (female/male 6/4; mean age 44.2 ± 10.5 years), previously recruited for different research studies 43,44,49 …”

Section: Methodsmentioning

confidence: 99%

“…11 C‐PK11195 is the first, prototypical PET tracer for the in vivo detection of the 18‐kDa translocator protein (TSPO), an outer mitochondrial membrane protein which is overexpressed in activated microglia and reactive astrocytes, thus becoming a sensitive marker of neuroinflammation 35 . A TSPO overexpression as detected by 11 C‐PK11195 PET has been reported in several neurodegenerative disorders, such as Alzheimer’s disease and other neurodegenerative dementias, prion diseases, Parkinson’s disease, as well as in sALS 36–45 . In addition, 11 C‐PK11195 PET studies showed microglia activation also in preclinical stages of neurodegenerative conditions, 43,46,47 shedding light on the possible early molecular mechanisms of neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Tondo

Iaccarino

Cerami

et al. 2020

Ann Clin Transl Neurol

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Objective Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11C‐PK11195 is the prototypical and most validated PET radiotracer, targeting the 18‐kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11C‐PK11195 and PET imaging. Methods We included 20 subjects: 4 ASYM‐carriers, neurologically normal, 6 SYM‐carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11C‐PK11195 binding potentials and voxel‐wise statistical comparisons were performed at group and single‐subject levels. Results Both the SYM‐ and ASYM‐carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM‐carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. Interpretation In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1‐ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Tondo

Iaccarino

Cerami

et al. 2020

Ann Clin Transl Neurol

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“…Sleep deprivation may increase the risk of inflammation and infection by altering immune function, whereas napping or extending sleep can restore immune system homeostasis [ 26 , 27 ]. Various studies have reported that microglia became activated in the brains of sleep-deprived mice, and the number and morphology of microglia were significantly positively correlated with neuronal apoptosis [ 28 , 29 ]. In this study, we found that NAR could effectively alleviate cell proliferation induced by LPS, suggesting that NAR may play a protective role by inhibiting microglia proliferation.…”

Section: Discussionmentioning

confidence: 99%

Naringin Regulates Microglia BV-2 Activation and Inflammation via the JAK/STAT3 Pathway

Liu

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Objective. Microglial BV-2 cells are activated in the brain following insomnia. Naringin (NAR) is a polymethoxylated flavonoid that is also commonly found in citrus fruits and is known for its antioxidant potential. However, the effect of NAR on microglial cells has rarely been studied in the brain of an organism after insomnia. This study aimed to investigate the effects and potential mechanisms of action of NAR on microglial cell activation and inflammation. Methods. BV-2 cells were obtained from the China Center for Type Culture Collection and randomly divided into five treatment groups: control, model, NAR (10 μM), WP1066 (5 μM), and NAR + WP1066. With the exception of the control group, all groups were stimulated with LPS (1 μg/mL) for 6 h. CCK8 was used to quantify cell viability and a scratch test was performed to detect cell migration. The expression levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), nterleukin 10 (IL-10), and insulin like growth factor (1IGF-1) were measured by ELISA. Western blotting was performed to determine the levels of p-STAT3 and p-JAK. The Focalcheck™ Thin-Ring Fluorescent Microspheres kit was used to detect cell phagocytosis. Immunofluorescence was used to observe the expression of iNOS and arginase1 in BV-2 cells. Results. Compared with the control group, cell migration, cell viability, and the expression of IL-1β, IL-6, TNF-α, and iNOS were significantly increased in the model group, whereas the expression levels of IL-10, IGF-1, and arginase 1, as well as cell phagocytosis were reduced. With the increase in NAR concentration, cell migration, cell viability, the expression levels of IL-1β, IL-6, TNF-α, and iNOS decreased, while the expression of IL-10, IGF-1, and arginase 1 increased. Compared with the control group, p-STAT3, and p-JAK expression in the model group were significantly increased (P<0.05). Compared with the model group, the expression of p-STAT3 and p-JAK in the NAR, NAR + WP1066, and WP1066 groups was significantly decreased ( P < 0.05 ). Conclusion. NAR treatment inhibited the proliferation, migration, and inflammation of BV-2 cells as well as the activation of microglia to the M1 phenotype. Conversely, NAR treatment promoted the activation of microglia to the M2 phenotype and enhanced the phagocytic function of BV-2 cells by regulating the activity of the JAK/STAT3 pathway.

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“…A single research group published two ( R )-[ 11 C]PK11195 reports that showed increased TSPO with varying patterns across subtypes of Creutzfeldt-Jakob disease [ 83 ] or Fatal Familial Insomnia [ 84 ]. There is no report using other radiotracers.…”

Section: Discussion On Each Group Of Diseasementioning

confidence: 99%

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

Chauveau

Becker

Boutin

2021

Eur J Nucl Med Mol Imaging

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Purpose The prototypical TSPO radiotracer (R)-[11C]PK11195 has been used in humans for more than thirty years to visualize neuroinflammation in several pathologies. Alternative radiotracers have been developed to improve signal-to-noise ratio and started to be tested clinically in 2008. Here we examined the scientific value of these “(R)-[11C]PK11195 challengers” in clinical research to determine if they could supersede (R)-[11C]PK11195. Methods A systematic MEDLINE (PubMed) search was performed (up to end of year 2020) to extract publications reporting TSPO PET in patients with identified pathologies, excluding studies in healthy subjects and methodological studies. Results Of the 288 publications selected, 152 used 13 challengers, and 142 used (R)-[11C]PK11195. Over the last 20 years, the number of (R)-[11C]PK11195 studies remained stable (6 ± 3 per year), but was surpassed by the total number of challenger studies for the last 6 years. In total, 3914 patients underwent a TSPO PET scan, and 47% (1851 patients) received (R)-[11C]PK11195. The 2 main challengers were [11C]PBR28 (24%—938 patients) and [18F]FEPPA (11%—429 patients). Only one-in-ten patients (11%—447) underwent 2 TSPO scans, among whom 40 (1%) were scanned with 2 different TSPO radiotracers. Conclusions Generally, challengers confirmed disease-specific initial (R)-[11C]PK11195 findings. However, while their better signal-to-noise ratio seems particularly useful in diseases with moderate and widespread neuroinflammation, most challengers present an allelic-dependent (Ala147Thr polymorphism) TSPO binding and genetic stratification is hindering their clinical implementation. As new challengers, insensitive to TSPO human polymorphism, are about to enter clinical evaluation, we propose this systematic review to be regularly updated (living review).

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An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

Cited by 10 publications

References 48 publications

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Naringin Regulates Microglia BV-2 Activation and Inflammation via the JAK/STAT3 Pathway

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

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An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

Cited by 10 publications

References 48 publications

11C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

11C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Naringin Regulates Microglia BV-2 Activation and Inflammation via the JAK/STAT3 Pathway

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

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Resources

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An in vivo ¹¹C‐PK PET study of microglia activation in Fatal Familial Insomnia

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis