Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study

Turner, Martin R; Cagnin, Annachiara; Turkheimer, Federico; Miller, Christopher C.J.; Shaw, Christopher E.; Brooks, David J.; Leigh, P. Nigel; Bánati, Richard B.

doi:10.1016/j.nbd.2003.12.012

Cited by 640 publications

(499 citation statements)

References 80 publications

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“…Rate of disability progression (ΔALSFRS‐R) was calculated as the decrease in ALSFRS‐R from a presumed baseline score of 48, divided by the disease duration in months from reported symptom onset. A measure of the burden of clinical UMN signs was based upon a pathological reflex sum score [Menke et al, 2014; Turner et al, 2004]…”

Section: Methodsmentioning

confidence: 99%

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Proudfoot

Rohenkohl

Quinn

et al. 2016

Human Brain Mapping

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Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Proudfoot

Rohenkohl

Quinn

et al. 2016

Human Brain Mapping

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“…The cerebellum has been used previously (Groom et al, 1995;Banati et al, 1999;Versijpt et al, 2003;Gerhard et al, 2005a), while an unaffected region was chosen to approximate those areas that would be found by cluster analysis as used in several reports (Banati et al, 2000(Banati et al, , 2001Cagnin et al, 2001a, b;Gerhard et al, 2003;Turner et al, 2004). Both these reference regions might, however, not be 'perfect' as reference tissue, because increased specific binding in these structures cannot be excluded.…”

Section: Limitationsmentioning

confidence: 99%

“…Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue model (SRTM) (Lammertsma and Hume, 1996) or by using uptake normalized to a reference region.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies

Kropholler

Boellaard

Schuitemaker

et al. 2006

J Cereb Blood Flow Metab

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[ 11 C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K 1 /k 2 fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM pl_corr ) was investigated. Correlations between reference tissue models (including SRTM pl_corr ) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM pl_corr performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM pl_corr and SRTM had the highest correlations with the plasma input model (R 2 = 0.82 and 0.78, respectively). SRTM pl_corr is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available. Keywords: microglia; peripheral benzodiazepine receptor; PET (positron emission tomography); PK11195; reference tissue models; tracer kinetic modelling IntroductionCarbon-11 labeled (R)-PK11195 ((R)-1-(2-chlorophenyl)-N-[ 11 C]methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor. In the brain, this receptor is mainly expressed on activated microglia (Banati et al, 1997). Both [ 11 C](R)-PK11195 and [ 11 C]PK11195 have been used as positron emmision tomography (PET) tracers to study activated microglia in various neurologic disorders. It has been used to study stroke (Ramsay et al, 1992;Pappata et al, 2000;Gerhard et al, 2000Gerhard et al, , 2005a), Alzheimer's disease (Groom et al, 1995; Cagnin et al, 2001a;Versijpt et al, 2003), multiple sclerosis (Banati et al, 2000;Debruyne et al, 2002Debruyne et al, , 2003Versijpt et al, 2005) and various other diseases (Pappata et al, 1991; Banati et al, 1999Banati et al, , 2001Goerres et al, 2001;Cagnin et al, 2001bCagnin et al, , 2004Cicchetti et al, 2002;Gerhard et al, 2003Gerhard et al, , 2004Gerhard et al, , 2005bTurner et al, 2004Turner et al, , 2005Venneti et al, 2004;Henkel et al, 2004;Ouchi et al, 2005). Most studies have used a reference tissue approach to quantify binding, either by applying the simplified reference tissue mod...

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“…Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in ALS pathology; the presence of activated microglial cells, in regions of motor neuron damage, was reported both in patients with ALS and in mouse models of ALS where microgliosis is already present prior to disease onset [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2016

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Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1 G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.

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Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study

Cited by 640 publications

References 80 publications

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

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Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study

Cited by 640 publications

References 80 publications

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

Contact Info

Product

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Evaluation of Reference Tissue Models for the Analysis of [¹¹C](R)-PK11195 Studies