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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“Finally, of particular interest concerning the QA model and its further use in combination with PET techniques is that our observations are in line with in vivo PET finding on HD patients reporting a significant increase in [(11)C](R)PK11195 binding in striatal and extrastriatal areas, which significantly correlated w…”
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Background
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“For instance, neuropathological and positron emission tomography (PET) studies showed accumulation of reactive microglia in the brain of HD patients, a finding that is significantly correlated with the severity of the disease (Pavese et al., 2006).”
Background
Pathological characterization of T2*-weighted MRI contrast in the striatum of Huntington’s disease patients
Bulk, M., Hegeman-Kleinn, I. M., Kenkhuis, B., Suidgeest, E., van Roon‐Mom, W., Lewerenz, J., van Duinen, S. G., Ronen, I., & van der Weerd, L. (2020) · NeuroImage Clinical · doi:10.1016/j.nicl.2020.102498 · Cited by 19
“6 (36-74) Male/Female 2 / 4 6 / 18 CAG repeat length, mean ± SD (range) n.”
Mapping of Translocator Protein (18 kDa) in Peripheral Sterile Inflammatory Disease and Cancer through PET Imaging
Adhikari, A., Singh, P., Mahar, K. S., Adhikari, M., Adhikari, B., Zhang, M., & Tiwari, A. K. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00002 · Cited by 19
The Endocannabinoid System in the Physiology and Pathology of the Basal Ganglia
Gerdeman, G. L., & Fernández‐Ruíz, J. (2007) · Springer eBooks · doi:10.1007/978-0-387-74349-3_21 · Cited by 19
“The occurrence of reactive microgliosis is documented in the striatum of HD patients (Pavese et al., 2006), which would support that they also experience a possible induction or upregulation of CB 2 receptors – this would have interesting pharmacological implications in a disease with a poor therapeutic outcome.”
Background
Behavioral- and blood-based biomarkers for Huntington's disease: Studies on the R6/1 mouse model with prospects for early diagnosis and monitoring of the disease
Podlacha, M., Pierzynowska, K., Gaffke, L., Jerzemowska, G., Piotrowska, E., & Węgrzyn, G. (2022) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2022.100482 · Cited by 18
Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery
Uzuegbunam, B. C., Rummel, C. D., Librizzi, D., Culmsee, C., & Yousefi, B. H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417419 · Cited by 20
Could astrocytes be the primary target of an offending agent causing the primary degenerative diseases of the human central nervous system? A hypothesis
Sica, R. E. P. (2015) · Medical Hypotheses · doi:10.1016/j.mehy.2015.02.004 · Cited by 18
Molecular imaging of movement disorders
Lizárraga, K. J., Gorgulho, A. A., Chen, W., & Salles, A. A. D. (2016) · World Journal of Radiology · doi:10.4329/wjr.v8.i3.226 · Cited by 18
Huntington’s Disease: Pathogenic Mechanisms and Therapeutic Targets
Wright, D. J., Renoir, T., Gray, L. J., & Hannan, A. J. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-57193-5_4 · Cited by 17
Inflammatory changes in peripheral organs in the BACHD murine model of Huntington's disease
Valadão, P. A. C., Oliveira, B. D. S., Joviano‐Santos, J. V., Vieira, É. L. M., Rocha, N. P., Teixeira, A. L., Guatimosim, C., & de Miranda, A. S. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116653 · Cited by 18
Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype
Węgrzynowicz, M., Bichell, T. J., Soares, B., Loth, M. K., McGlothan, J. L., Alikhan, F. S., Hua, K., Coughlin, J. M., Holt, H. K., Jetter, C. S., et al. (2015) · Journal of Huntington s Disease · doi:10.3233/jhd-140116 · Cited by 18
Imaging neuroinflammation in Alzheimer’s and other dementias: recent advances and future directions
Brooks, D. J. (2016) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2016.01.049 · Cited by 17
Self-citation
Dysregulation of gene expression in the striatum of BACHD rats expressing full-length mutant huntingtin and associated abnormalities on molecular and protein levels
Yu-Taeger, L., von Bonin, M., Stricker-Shaver, J., Rieß, O., & Nguyen, H. P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.01.029 · Cited by 17
“Furthermore, growth factors including epidermal growth factor (EGF) and nerve growth factor (NGF), cytokines such as tumor necrosis factor (TNF) and interleukin 1 beta (ILB1) also accounted for the important upstream regulators in BACHD rats and human HD that showed considerable expression changes in the target genes…”
Background
RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease
Andrade-Navarro, M. A., Mühlenberg, K., Spruth, E. J., Mah, N., González-López, A., Andreani, T., Russ, J., Huska, M. R., Muro, E. M., Fontaine, J., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.573560 · Cited by 17
Increased penetration of diphenhydramine in brain via proton-coupled organic cation antiporter in rats with lipopolysaccharide-induced inflammation
Kawase, A., Chuma, T., Irie, K., Kazaoka, A., Kakuno, A., Matsuda, N., Shimada, H., & Iwaki, M. (2020) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2020.100188 · Cited by 17
Immunological aspects of central neurodegeneration
Niso‐Santano, M., Fuentes, J. M., & Galluzzi, L. (2024) · Cell Discovery · doi:10.1038/s41421-024-00666-z · Cited by 17
“Similar to AD and PD, HD is also characterized by microgliosis, both in humans 121 – 123 and in mouse models of the disease such as R6/2 mice 124 – 126 .”
[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model
Xie, L., Yamasaki, T., Ichimaru, N., Yui, J., Kawamura, K., Kumata, K., Hatori, A., Nonomura, N., Zhang, M., Li, X., et al. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9322-3 · Cited by 20
“Pharmacological probes that bind TSPO have been used extensively to study receptor-binding parameters in brain tissues (Pavese et al. 2006; Venneti et al. 2006; Toyama et al. 2008).”
Neuroinflammation as a therapeutic target in neurodegenerative diseases
Gordon, R., & Woodruff, T. M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805120-7.00003-8 · Cited by 19
Association Between Toll‐Like Receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Genetic Variants and Clinical Progression of Huntington's Disease
Vuono, R., Kouli, A., Legault, E. M., Chagnon, L., Allinson, K. S. J., Spada, A., REGISTRY Investigators of the European Huntington's Disease Network, Biunno, I., Barker, R. A., & Drouin‐Ouellet, J. (2019) · Movement Disorders · doi:10.1002/mds.27911 · Cited by 17
Self-citation
Decoding Microglial Polarization and Metabolic Reprogramming in Neurodegenerative Diseases: Implications for Disease Progression and Therapy
Gao, R., Gao, Y., Su, W., & Wang, R. (2025) · Aging and Disease · doi:10.14336/ad.2024.1629 · Cited by 18
“This polarization of microglia alters their functions and promotes neuroinflammation, a key factor in the progression of HD [201,202].”
Therapeutic Delivery of Simvastatin Loaded in PLA-PEG Polymersomes Resulted in Amplification of Anti-inflammatory Effects in Activated Microglia
Manickavasagam, D., Novak, K. M., & Oyewumi, M. O. (2017) · The AAPS Journal · doi:10.1208/s12248-017-0176-3 · Cited by 16
“multiple sclerosis (MS) (9), and Huntington’s disease (HD) (10).”
Background
Tracing the History of the Human Translocator Protein to Recent Neurodegenerative and Psychiatric Imaging
Downer, O. M., Marcus, R. E. G., Zürcher, N. R., & Hooker, J. M. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00362 · Cited by 15
Cell Reprogramming to Model Huntington’s Disease: A Comprehensive Review
Monk, R., & Connor, B. J. (2021) · Cells · doi:10.3390/cells10071565 · Cited by 19
“While MSNs are preferentially affected in HD, astrocytes [142–146], microglia [147,148], and oligodendrocytes have all been implicated in HD neuropathogenesis, especially during the later disease stages.”
Background
Inflammasome activation and assembly in Huntington’s disease
Furlam, T. D. O., Roque, I. G., da Silva, E. W. M., Vianna, P. P., Valadão, P. A. C., Guatimosim, C., Teixeira, A. L., & de Miranda, A. S. (2022) · Molecular Immunology · doi:10.1016/j.molimm.2022.09.002 · Cited by 16
4'-Chlorodiazepam is neuroprotective against amyloid-beta through the modulation of survivin and bax protein expression in vitro.
Arbo, B. D., Marques, C. V., Ruiz-Palmero, I., Ortiz-Rodriguez, A., Ghorbanpoor, S., Arevalo, M., Garcia-Segura, L., & Ribeiro, M. (2016) · Brain Research · doi:10.1016/j.brainres.2015.12.018 · Cited by 2
The role of microglia in neurodegenerative diseases
Nie, D.-A., Yu, J., Huang, W., Li, G., He, X., & Xu, J.-H. (2025) · Molecular Immunology · doi:10.1016/j.molimm.2025.07.014 · Cited by 16
Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington’s disease
van de Zande, N. A., Bulk, M., Najac, C., van der Weerd, L., de Bresser, J., Lewerenz, J., Ronen, I., & de Bot, S. T. (2023) · NeuroImage Clinical · doi:10.1016/j.nicl.2023.103450 · Cited by 16
“Previous studies, focusing on iron accumulation in neurodegenerative diseases such as Alzheimer’s disease as well as HD, have shown that iron appears to be absorbed by activated microglia, the resident macrophages of the brain (Meadowcroft et al., 2015; Thomsen et al., 2015; Zeineh et al., 2015; Pavese et al., 2006; S…”
Background
Naïve Huntington’s disease microglia mount a normal response to inflammatory stimuli but display a partially impaired development of innate immune tolerance that can be counteracted by ganglioside GM1
Steinberg, N., Galleguillos, D., Zaidi, A. K., Horkey, M., & Sipione, S. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02963-y · Cited by 14
Microglia in Neurodegenerative Diseases
Awogbindin, I. O., Wanklin, M., Verkhratsky, A., & Tremblay, M. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_27 · Cited by 14
RETRACTED: Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum
Menze, E. T., Esmat, A., Tadros, M. G., Khalifa, A. E., & Abdel‐Naim, A. B. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.01.007 · Cited by 13
“It is well-known that activated microglia releases proinflammatory mediators like cytokines, excitatory amino acid and increases the expression of COX-2 and iNOS, which further enhances the production of superoxides and nitric oxides (Pavese et al., 2006; Tai et al., 2007).”
Background
Retracted
Huntington’s Disease Pathogenesis: Mechanisms and Pathways
Spada, A. R. L., Weydt, P., & Pineda, V. V. (2011) · Europe PMC (PubMed Central) · Cited by 13
Molecular Imaging in Huntington's Disease
Wilson, H., & Politis, M. (2018) · International review of neurobiology · doi:10.1016/bs.irn.2018.08.007 · Cited by 12
Neurodegenerative Diseases
Gómez‐Nicola, D., & Perry, V. H. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1429-6_18 · Cited by 13
Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery
Ceccarelli, I., Fiengo, P., Remelli, R., Miragliotta, V., Rossini, L., Biotti, I., Cappelli, A., Petricca, L., Rosa, S. L., Caricasole, A., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.11.019 · Cited by 14
“Initial studies showed that microglia activation in HD patients correlates with disease progression as assessed by loss of dopamine D2 receptor binding sites (Pavese et al., 2006; Tai et al, 2007).”
Activated macrophages in HIV encephalitis and a macaque model show increased [3H](R)-PK11195 binding in a PI3-kinase-dependent manner
Venneti, S., Wang, G., & Wiley, C. A. (2007) · Neuroscience Letters · doi:10.1016/j.neulet.2007.08.053 · Cited by 13
“These data are in agreement with a large body of work that report increased PK11195 binding corresponding to activated brain macrophages, as determined using PET, in several acute and chronic neuroinflammatory conditions such as stroke [27], multiple sclerosis [2], Alzheimer’s disease [4], Parkinson’s disease [22], an…”
Result
Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia
Stöberl, N., Donaldson, J., Binda, C. S., McAllister, B., Hall‐Roberts, H., Jones, L., Massey, T. H., & Allen, N. D. (2023) · Scientific Reports · doi:10.1038/s41598-023-46852-z · Cited by 15
Neuroimaging to Facilitate Clinical Trials in Huntington’s Disease: Current Opinion from the EHDN Imaging Working Group
Hobbs, N. Z., Papoutsi, M., Delva, A., Kinnunen, K. M., Nakajima, M., Laere, K. V., Vandenberghe, W., Herath, P., & Scahill, R. I. (2024) · Journal of Huntington s Disease · doi:10.3233/jhd-240016 · Cited by 11
“Also,striatalTSPObindingcor-relatedpositivelywithmotorimpairment[61,161] anddiseaseburdenscore[61].”
The mitochondrial translocator protein (TSPO) in Alzheimer's disease: Therapeutic and immunomodulatory functions
Fairley, L. H., Lai, K. O., Grimm, A., Eckert, A., & Barron, A. M. (2024) · Biochimie · doi:10.1016/j.biochi.2024.07.003 · Cited by 14
Challenges of Huntington's disease and quest for therapeutic biomarkers
Kotrčová, E., Jarkovská, K., Valeková, I., Žižková, M. (., Motlík, J., Gadher, S. J., & Kovářová, H. (2014) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.201400073 · Cited by 12
“Furthermore, in vivo imaging indicated that microglia activation appeared in the brains of presymptomatic HD subjects [43, 46] and that microglial reactivity consistently increased with the disease severity [47].”
Background
Free Radicals and Oxidative Stress in Neurodegenerative Disorders
Nigam, D. (2014) · Springer eBooks · doi:10.1007/978-81-322-2035-0_11 · Cited by 13
Mechanisms underlying neurodegeneration in Huntington disease: applications to novel disease-modifying therapies
Ross, C. A., Kronenbuerger, M., Duan, W., & Margolis, R. L. (2017) · Handbook of clinical neurology · doi:10.1016/b978-0-12-801893-4.00002-x · Cited by 14
Micrandilactone C, a Nortriterpenoid Isolated from Roots of Schisandra chinensis, Ameliorates Huntington’s Disease by Inhibiting Microglial STAT3 Pathways
Jang, M., Choi, J. H., Jang, D. S., & Cho, I. (2023) · Cells · doi:10.3390/cells12050786 · Cited by 12
“Clinical studies using positron emission tomography have also demonstrated that the level of microglial activation is increased in proportion to the severity of HD symptoms [38,42].”
Background

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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