Cited by 473Genetic Neurodegenerative DiseasesNeuroinflammation and Neurodegeneration MechanismsNeurological diseases and metabolism

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Microglial activation correlates with severity in Huntington disease: A clinical and PET study

Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., Brooks, D. J., Piccini, P.·2006·Neurology

DOI 10.1212/01.wnl.0000222734.56412.17

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Abstract

BACKGROUND: Huntington disease (HD) is characterized by the progressive death of medium spiny dopamine receptor bearing striatal GABAergic neurons. In addition, microglial activation in the areas of neuronal loss has recently been described in postmortem studies. Activated microglia are known to release neurotoxic cytokines, and these may contribute to the pathologic process. METHODS: To evaluate in vivo the involvement of microglia activation in HD, the authors studied patients at different stages of the disease using [(11)C](R)-PK11195 PET, a marker of microglia activation, and [(11)C]raclopride PET, a marker of dopamine D2 receptor binding and hence striatal GABAergic cell function. RESULTS: In HD patients, a significant increase in striatal [(11)C](R)-PK11195 binding was observed, which significantly correlated with disease severity as reflected by the striatal reduction in [(11)C]raclopride binding, the Unified Huntington's Disease Rating Scale score, and the patients' CAG index. Also detected were significant increases in microglia activation in cortical regions including prefrontal cortex and anterior cingulate. CONCLUSIONS: These [(11)C](R)-PK11195 PET findings show that the level of microglial activation correlates with Huntington disease (HD) severity. They lend support to the view that microglia contribute to the ongoing neuronal degeneration in HD and indicate that [(11)C](R)-PK11195 PET provides a valuable marker when monitoring the efficacy of putative neuroprotecting agents in this relentlessly progressive genetic disorder.

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Background
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Background
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Background
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Background
11C-PK11195 PET for the In Vivo Evaluation of Neuroinflammation in the Rat Brain After Cortical Spreading Depression
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“11C-labeled PK11195, a ligand that specifically binds to PBR, has been used extensively for imaging of activated microglial cells by PET in several neurologic disorders, such as stroke (14), multiple sclerosis (15), Alzheimer disease (16), Parkinson disease (17), and Huntington disease (18).”
Background
Molecular Imaging Markers to Track Huntington’s Disease Pathology
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A Critical Evaluation of Wet Biomarkers for Huntington’s Disease: Current Status and Ways Forward
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Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology
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Targeting Neuro-Inflammatory Cytokines and Oxidative Stress by Minocycline Attenuates Quinolinic-Acid-Induced Huntington’s Disease-Like Symptoms in Rats
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“…may play a major role in the pathogenesis of HD has been shown to correlate with severity of the disease, with a close spatial and temporal relationship to neuronal dysfunction (Pavese et al. 2006; Tai et al. 2007), and has already been detected in presymptomatic HD gene carriers (Tai et al. 2007).”
Background
Targeting Glial Cells to Elucidate the Pathogenesis of Huntington’s Disease
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“Most importantly, activation of microglia can be observed at the presymptomatic stage [36, 37], suggesting that microglial activation is an early incident in the progression of HD. Moreover, microglial activation appears to be correlated with the severity of the disease in both HD patients and mice [36, 79 ].”
Background
Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson’s Disease
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PET Image Denoising Using a Synergistic Multiresolution Analysis of Structural (MRI/CT) and Functional Datasets
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“For this study we selected a set of 22 [11C]-(R)-PK11195 scans, 12 of which were performed on HD patients with overt symptoms and 10 were age-matched controls (18).”
MethodSelf-citation
Microglial Adenosine Receptors: From Preconditioning to Modulating the M1/M2 Balance in Activated Cells
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Background
The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases
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Valproic acid induces microglial dysfunction, not apoptosis, in human glial cultures
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“Neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, motor neuron disease, Huntington's disease and temporal lobe epilepsy are associated with proliferation and activation of microglia (Liu and Hong, 2003; Minghetti, 2005; Pavese et al., 2006; Sauvageau et al., 2002).”
Background
Anti-inflammatory effects of ellagic acid and vanillic acid against quinolinic acid-induced rat model of Huntington's disease by targeting IKK-NF-κB pathway
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An Alteration in the Lateral Geniculate Nucleus of Experimental Glaucoma Monkeys: In vivo Positron Emission Tomography Imaging of Glial Activation
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“A non-invasive PET imaging with [(11)C]PK11195 for activated microglial cells has been extensively used in several neurodegenerative disorders, such as multiple sclerosis [25], Alzheimer disease [26], Parkinson disease [27], and Huntington disease [28].”
Method
Effects of Translocator Protein (18 kDa) Ligands on Microglial Activation and Neuronal Death in the Quinolinic-Acid-Injected Rat Striatum
Leaver, K. R., Reynolds, A. J., Bodard, S., Guilloteau, D., Chalon, S., & Kassiou, M. (2011) · ACS Chemical Neuroscience · doi:10.1021/cn200099e · Cited by 48
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Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue to Intervene in Disease Progression
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TSPO–PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington’s disease: preclinical evidence with the p75NTR ligand LM11A-31
Simmons, D. A., James, M. L., Belichenko, N. P., Semaan, S., Condon, C., Kuan, J., Shuhendler, A. J., Miao, Z., Chin, F. T., & Longo, F. M. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy202 · Cited by 44
“In studies of HD patients, the [(11)C]PK11195-PET signal correlated with striatal dopamine receptor (D2) loss and motor symptom severity in manifest stages (42), and with cognitive deficits in the associative striatum and an increased probability of symptom onset in premanifest stages (44,45).”
Background
Protective effect of naringin on 3-nitropropionic acid-induced neurodegeneration through the modulation of matrix metalloproteinases and glial fibrillary acidic protein
Gopinath, K., & Sudhandiran, G. (2015) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2015-0035 · Cited by 43
Immunotherapies in Huntington's disease and α-Synucleinopathies
Fatoba, O., Ohtake, Y., Itokazu, T., & Yamashita, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00337 · Cited by 45
A systematic comparison of kinetic modelling methods generating parametric maps for [11C]-(R)-PK11195
Anderson, A. N., Pavese, N., Edison, P., Tai, Y., Hammers, A., Gerhard, A., Brooks, D. J., & Turkheimer, F. (2007) · NeuroImage · doi:10.1016/j.neuroimage.2007.02.017 · Cited by 42
“…to make use of a previously-published dataset of Huntington’s disease (HD) patients with genetically proven disease and clinically overt symptoms (Pavese et al., 2006) where a well defined pattern of microglial activation in basal ganglia plus Table 1C Test–retest results for DEPICT Kinetic…”
BackgroundMethodInfluentialSelf-citation
Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF ‐ 1R
Guenoun, D., Blaise, N., Sellam, A., Roupret‐Serzec, J., Jacquens, A., Steenwinckel, J. V., Gressèns, P., & Bokobza, C. (2024) · Glia · doi:10.1002/glia.24664 · Cited by 41
Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease
Mendell, A. L., & MacLusky, N. J. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00359 · Cited by 46
“…et al., 2005; Chen et al., 2011; Frye and Paris, 2011), while the testosterone metabolite 3αdiol has been shown to have negligible affinity for the androgen receptor (AR) and weak affinity for estrogen receptor β (ERβ; Liao et al., 1973; Kuiper et al., 1997; Penning, 1997; Edinger and Frye, 2007).”
Background
Human Huntington’s disease pluripotent stem cell-derived microglia develop normally but are abnormally hyper-reactive and release elevated levels of reactive oxygen species
O’Regan, G. C., Farag, S. H., Casey, C. S., Wood‐Kaczmar, A., Pocock, J. M., Tabrizi, S. J., & André, R. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02147-6 · Cited by 44
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Background
The unfolded protein response and its potential role in Huntington ́s disease elucidated by a systems biology approach
Kalathur, R. K. R., Giner‐Lamia, J., Machado, S., Barata, T., Ayasolla, K., & Futschik, M. E. (2015) · F1000Research · doi:10.12688/f1000research.6358.2 · Cited by 47
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Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease
Garcia‐Miralles, M., Yusof, N. A. B. M., Tan, J. Y., Radulescu, C. I., Sidik, H., Tan, L. J., Belinson, H., Zach, N., Hayden, M. R., & Pouladi, M. A. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1393-1 · Cited by 40
Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats
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Preclinical Imaging Evaluation of Novel TSPO-PET Ligand 2-(5,7-Diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1008) in Glioma
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“Accordingly, TSPO expression is elevated in several clinically important disease states, including Alzheimer’s disease [7, 8], Huntington’s disease [9], Parkinson’s disease [10], and cancer.”
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Interleukin-19 Acts as a Negative Autocrine Regulator of Activated Microglia
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Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica
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Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice
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Laquinimod dampens hyperactive cytokine production in Huntington's disease patient myeloid cells
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Authors: Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., Brooks, D. J., & Piccini, P.
Affiliations: Hammersmith Hospital (GB)
ORCID: Pavese, N.
Gerhard, A.
Tai, Y. F.
Ho, A. K.
Turkheimer, F.
Barker, R. A.
Brooks, D. J.
Piccini, P.
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-06-13
Volume: 66
Issue: 11
Pages: 1638-1643
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/01.wnl.0000222734.56412.17
OpenAlex: W2025681964
Cited by: 462
References: 35
Citations by year: 2026: 12 · 2025: 19 · 2024: 30 · 2023: 26 · 2022: 22 · 2021: 26 · 2020: 27 · 2019: 19 · 2018: 18 · 2017: 31 · 2016: 25 · 2015: 25 · 2014: 38 · 2013: 19 · 2012: 14
FWCI: 8.08
Type: journal article
Language: en
Open access: closed
Locations: Neurology (publishedVersion)
PubMed (publishedVersion)
CentAUR (University of Reading) (acceptedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
Funders: Wellcome Trust
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
Keywords: Huntington's disease, microglial activation, dopamine D2 receptor binding, disease severity, neuroinflammation, neurodegeneration, prefrontal cortex, anterior cingulate cortex, CAG repeat expansion
MeSH terms: Adult, Aged, Amides, Corpus Striatum, Female, Humans, Huntington Disease, Isoquinolines, Male, Middle Aged, Sensitivity and Specificity, Severity of Illness Index, Statistics as Topic, Reproducibility of Results, Microglia, Radiopharmaceuticals, Raclopride, Positron-Emission Tomography

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Microglial activation correlates with severity in Huntington disease: A clinical and PET study

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