Abstract
The potential contribution of neuroinflammation to CNS injury in neurodegenerative diseases (NDDs) has been extensively evaluated using molecular imaging with PET, with most studies focusing on Alzheimer’s disease (AD), while fewer studies evaluated Parkinson’s disease (PD) and other movement disorders. By far, the most commonly studied neuroinflammation target with PET has been the 18-kDa translocator protein (TSPO), an outer mitochondrial membrane receptor that is expressed in many CNS and peripheral immune cells and is upregulated in neuroinflammatory states. PET imaging of TSPO, however, has several limitations. As a result, multiple alternative biological targets and radioligands for imaging neuroinflammation are being developed and may prove superior in the assessment of pro- and anti-inflammatory activity in NDDs. The overarching goals of available and future studies are to understand the role of neuroinflammation in NDD pathophysiology and progression, monitor treatment effects, and provide surrogate endpoints in clinical trials to modify neuroinflammation.
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Keywords
- Neuroinflammation
- Molecular imaging
- Positron emission tomography
- Neurodegenerative diseases
- Alzheimer’s disease
- Parkinson’s disease
Introduction
Neuroinflammation is a natural response of a competent immune system to any type of CNS insult, and it includes both innate (e.g., monocytes) and adaptive components (lymphocytes). A special characteristic of the CNS is the presence of specialized resident immune cells, the microglia. When faced with a noxious stimulus or injury, microglial cells become activated, increase in size, assume an ameboid shape with shorter processes, and secrete a variety of cytokines and other neurotoxic compounds. An excessive reaction can result in a vicious cycle that eventually results in neuronal injury and death. Microglial activation, however, is only one part of the neuroinflammatory process, with additional contributions from astrocytes, peripherally derived macrophages, and sometimes T-cell lymphocytes (Fig. 9.1).
The potential contribution of neuroinflammation to CNS injury has been extensively studied using molecular imaging with positron emission tomography (PET) in many disease entities, including neurodegenerative diseases (NDDs). Most research using neuroinflammation imaging in NDDs has focused on Alzheimer’s disease (AD), with fewer studies evaluating Parkinson’s disease (PD) and other movement disorders. The overarching goal of such studies is to understand the role of neuroinflammation in disease pathophysiology and progression. Imaging can also be used to monitor treatment effects and to provide surrogate endpoints in clinical trials of strategies to modify neuroinflammation. While there are many targets that could be used to image neuroinflammation with PET, the most commonly studied target has been the 18-kDa translocator protein (TSPO), an outer mitochondrial membrane receptor that is expressed in many CNS and peripheral immune cells [1]. Basal TSPO expression in the brain parenchyma is low but it is upregulated in inflammatory states. As a result, imaging TSPO has been used to assess the neuroinflammatory process in various diseases including NDDs, and many radioligands have been developed to image TSPO with PET.
However, TSPO as a target to monitor neuroinflammation does have several shortcomings. In the CNS, TSPO is expressed in several cell types. These include resident microglia and monocyte-derived macrophages, astrocytes, and endothelial, choroid plexus and ependymal cells, with low but ubiquitous expression in the parenchyma [2]. Although generally assumed not to be expressed in neurons, colocalization of TSPO staining with tyrosine hydroxylase has been reported, raising the possibility that dopaminergic neurons also express TSPO [3]. TSPO imaging also cannot distinguish between activated microglia that are harmful (pro-inflammatory M1 phenotype) versus neuroprotective (anti-inflammatory M2), and cannot differentiate microglia from astrocytes, which also participate in the neuroinflammatory process.
The original and most commonly used TSPO PET ligand is [11C]-PK11195, an isoquinolone TSPO antagonist. However, it has several limitations as a PET radiotracer, including low blood–brain barrier permeability and high binding to plasma proteins, limiting tracer entry to brain, and low specific binding to the TSPO target with a poor signal-to-noise ratio in the PET images. As a result, many other ligands have since been and continue to be developed to improve neuroinflammation imaging (Fig. 9.2).
In general, TSPO ligands other than [11C]-PK11195 are referred to as second- or third-generation ligands (Fig. 9.2), with improved affinity and higher specific-to-nonspecific binding. The use of second-generation ligands, however, was immediately hampered because almost 10% of subjects showed no specific binding. Upon further evaluation, a polymorphism was discovered in exon 4 of the TSPO gene resulting in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr). This resulted in three possible binding levels: high-affinity binders (HAB) (C/C; Ala/Ala), medium-affinity binders (MAB) (C/T; Ala/Thr), and low-affinity binders (LAB) (T/T; Thr/Thr) [4, 5]. This necessitates genotyping before imaging and exclusion of almost 10% of the population, as well as the need to increase the sample number to match the binding levels between patients and controls.
Multiple third-generation ligands have subsequently been developed with claims of lower or no sensitivity to polymorphism [6, 7]. However, to our knowledge no ligand has been found that is completely insensitive to polymorphism.
Imaging Neuroinflammation in Alzheimer’s Disease
One reason neuroinflammation has been considered a possible factor in the pathophysiology of AD is that the amyloid-β deposition hypothesis seems to be insufficient to explain all aspects of disease pathogenesis. In addition, increased inflammatory markers have been described in AD, and the AD risk genes such as ApoE are known to be associated with innate immune function modulation [8]. Therefore, PET has been widely used to assess the role of neuroinflammation in AD pathogenesis. These PET studies typically include imaging with radiotracers for amyloid and tau to confirm the stage and relation to neuroinflammation of the underlying AD pathophysiological process. Unfortunately, the results of these studies have generally been inconsistent.
Two early studies using [11C]-PK11195 suggested a role for neuroinflammation in AD and mild cognitive impairment (MCI). Cagnin et al. found that while in controls regional binding significantly increased with age in the thalamus, patients with AD showed significantly increased binding in the entorhinal, temporoparietal, and cingulate cortex [9]. Okello et al. showed that amyloid deposition and microglial activation can be detected in about 50% of patients with MCI. However, there was no correlation between regional levels of [11C]-PK11195 and amyloid, suggesting that the two pathologies can co-exist but can also occur independently [10].
Many later studies using second-generation ligands often showed discordant results. Yasuno et al. showed increased [11C]-DAA1106 binding in 10 AD patients [11] and Kreisl et al. found elevated [11C]-PBR28 binding in AD but not in MCI [12]. Two other papers, however, using [11C]-vinpocetine and [18F]-FEDAA1106, showed no difference between AD subjects and age-matched controls [13, 14]. Interestingly, Kreisl et al. found a correlation between neuroinflammation (measured by [11C]-PBR28) and amyloid (imaged with [11C]-PIB), and between neuroinflammation and neurocognitive impairment in AD (although not in MCI patients), contrary to the findings of Okello et al. [10]. Since increased binding of [11C]-PBR28 was seen only in AD, the authors proposed that neuroinflammation occurs after conversion of MCI to AD and worsens with disease progression, thus making its detection possibly useful in marking the conversion from MCI to AD and in assessing response to experimental treatments.
More recently, many studies using either [11C]-PK11195 or second-generation ligands to assess MCI and AD also demonstrated conflicting results. Some showed no correlation between inflammation, cognition and/or pathologic correlates (amyloid and/or tau burden) [15,16,17]. However, others showed the opposite, albeit to different degrees or distributions, e.g., in different brain regions or using a global measure of neuroinflammation [18,19,20,21,22,23,24,25].
There are several possible explanations for these discrepant results. The use of different ligands with different imaging characteristics and sensitivities to detect TSPO expression likely is a major factor. This was elegantly demonstrated by Yokokura et al. who used the “gold standard” of receptor blocking experiments to determine the specific binding of two TSPO radiotracers. While [11C]-PK11195 showed small differences between AD and controls in the precuneus, imaging with [11C]-DPA713 demonstrated more impressive increased binding in multiple regions including the anterior and posterior cingulate gyri, thalamus, and precuneus [26] (Fig. 9.3).
Another factor likely underlying the conflicting PET imaging results is the use of different patient populations at different stages of the AD pathophysiological process, often with small sample numbers. A third factor is the use of different image analysis methods to estimate the level of TSPO binding. These include graphical analysis with a measured arterial plasma input function (e.g., [19]), simplified reference tissue methods with various brain regions used to provide information about the delivery of radiotracer to tissue (e.g., [27]), or a semi-quantitative approach using the ratio of local regional radioactivity to radioactivity in the cerebellum which is assumed not to be affected by the disease process (e.g., [28]).
To help reconcile these results, Bradburn et al. performed a meta-analysis of TSPO studies in AD and MCI [29]. The authors concluded that neuroinflammation is increased in AD, with more modest effects in MCI. In the parietal region, the neuroinflammatory effects correlated with Mini-Mental State Examination scores in AD. This meta-analysis was published in 2019; the inclusion of more recent studies could provide different results.
Two such studies are noteworthy because they included a large number of subjects who were studied longitudinally [22, 30]. Hamelin et al. used [18F]-DPA714 to evaluate patients who were classified either as prodromal AD (amyloid positive, Clinical Dementia Rating (CDR) score = 0.5) or demented (amyloid positive, CDR ≥ 1.0 [30]). Follow-up scans in 1–2 years showed two distinctive dynamic patterns of microglial activation: higher initial [18F]-DPA714 binding followed by a slower increase in subjects with slower disease progression, and lower initial [18F]-DPA714 binding followed by a more rapid increase in subjects with accelerated disease progression. This suggested a possible protective role of microglial activation in early stages of AD. This was proposed by Leng and Edison who suggested that an initial microglial response might be protective, thus slowing disease progression (Fig. 9.4). However, subsequent chronic activation eventually causes phenotypic changes in microglia and shifts their behavior toward a pro-inflammatory phenotype, which causes damage to neuronal networks and disease progression. On the other hand, AD patients with defective microglial functioning at the onset of disease would undergo a quicker progression and an exaggerated late-stage inflammatory response [31].
Pascoal et al. imaged 130 HAB subjects over the normal aging and AD clinical spectrum, longitudinally, for TSPO expression and amyloid and tau levels. Neuroinflammation and tau pathology correlated hierarchically with each other following Braak-like stages of neuropathological disease progression. The strongest predictor of cognitive impairment was the co-occurrence of amyloid, tau, and microglial abnormalities. They concluded that amyloid and activated microglia interaction might determine the rate of tau spread across disease stages [22].
In conclusion, neuroinflammation seems to play an important role in the pathophysiology of AD, but a better understanding of this role is needed, especially since many trials of anti-inflammatory drugs did not slow disease progression [32,33,34]. This is key for future AD clinical trials to suppress pro-inflammatory changes or enhance microglial anti-inflammatory properties, along with anti-amyloid or -tau approaches. Imaging of neuroinflammation in AD should be further refined to serve as a quantitative surrogate endpoint in clinical trials.
Imaging Neuroinflammation in Parkinson’s Disease and Other Movement Disorders
Another NDD in which neuroinflammation is suspected to play a role is PD, which is characterized by the degeneration of dopaminergic neurons in the substantia nigra and the pathologic presence of abnormal cytoplasmic inclusions, Lewy bodies, containing alpha-synuclein. PD is classically described as a movement disorder, with bradykinesia, resting tremor, rigidity, and postural instability [35]. More recently, however, it is being thought of as a multi-system disorder, where neuroinflammation and immune dysfunction play a major role, and with non-motor symptoms such as sleep and mood disorders [36] and gastrointestinal dysfunction [37] preceding motor manifestations. Many PD patients also develop dementia in the later stages of the disease.
PET imaging of neuroinflammation in PD patients was first reported by Gerhard et al. who showed increased [11C]-PK11195 binding, although the degree of microglial activation did not correlate with clinical severity or putaminal [18F]-DOPA uptake [38]. A study using a second-generation ligand ([18F]-FEPPA), however, showed no effect of disease or disease x TSPO genotype interaction on ligand binding in any brain region [39]. Interestingly, the same group subsequently showed an interaction between neuroinflammation and amyloid deposition in PD with cognitive decline. They noted that further research is needed to determine whether amyloid deposits cause neuroinflammation and further neurodegeneration, or if increased microglia activation is a protective response [40]. These results likely overlap with prior work showing neuroinflammation in AD.
Using another second-generation ligand, [18F]-DPA714, a third group showed binding that suggested neuroinflammation in the nigrostriatal pathway, more so on the more affected side. However, this did not correlate with symptom severity, dopamine transporter (DAT) binding or disease duration. In the frontal cortex, neuroinflammation did correlate with disease duration [41]. The authors suggested this discrepancy between regions could reflect spreading of pathology in the later stage of the disease [41]. Finally, a study published in 2019 using [11C]-PBR28 in PD patients showed no neuroinflammation despite DAT imaging demonstrating dopaminergic degeneration [42].
A recent meta-analysis of neuroinflammation studies in PD clearly showed the effect of ligand choice on the results. While neuroinflammation was seen in multiple brain regions using [11C]-PK11195, only the midbrain showed significant increases when second-generation ligands were used [43]. Heterogeneity in results was found in many brain regions. This could be due to different ligands, different analysis approaches (e.g., the use of the cerebellum as a reference region), or suboptimal reporting of detailed clinical variables. Of note, the nonspecific binding of [11C]-PK11195 has been reported to be lower in PD patients; this could affect the results of certain analysis methods [44]. Therefore, there is a need for a more uniform approach to performing PET studies and for using large-cohort longitudinal studies to better understand the role of neuroinflammation in PD pathophysiology and progression.
Neuroinflammation imaging has been performed to a lesser extent in other NDDs. In Huntington’s disease, for example, several studies identified neuroinflammatory changes, mainly in the globus pallidus and putamen in affected patients [45,46,47]. In one study, even premanifest HD gene carriers showed increased TSPO expression, although the changes were not significant when compared to controls and affected subjects [46]. In another study, the authors observed further distinct regional and subregional imaging features, which seemed to correspond to phenotypical variability [45]. Imaging studies using first- and second-generation TSPO ligands also identified neuroinflammatory changes in progressive supranuclear palsy patients [23, 48, 49]. In a study by Palleis et al., patients with corticobasal degeneration were also included and showed even more extensive inflammatory changes compared to progressive supranuclear palsy (PSP) subjects. TSPO upregulation, however, was not correlated with measures of disease progression in either PSP or corticobasal degeneration [49]. This contradicts the findings of Malpetti et al., where neuroinflammation (measured with [11C]-PK11195) and tau burden in the brainstem and cerebellum correlated with the subsequent annual rate of PSP disease progression [50]. Additional work is thus needed to better understand the interaction between neuroinflammatory changes and disease progression in different NDDs.
Conclusions
The use of TSPO as an imaging target in NDDs and other CNS diseases remains challenging at multiple levels, and the interpretation of study results should be done with caution. A better understanding of the cellular regulation of TSPO expression and how it changes in relationship to disease progression in NDDs might help determine whether TSPO is an appropriate marker for those diseases, especially AD [51]. Meanwhile, alternative biological targets and radioligands for imaging neuroinflammation are being developed and may prove superior in the assessment of pro- and anti-inflammatory activity in NDDs [52]. One such radioligand is 11C-BU99008, a novel PET tracer that selectively targets activated astrocytes. A recent study showed higher 11C-BU99008 uptake in eight amyloid positive subjects compared to nine controls in the frontal, temporal, medial temporal, and occipital lobes (regions with high Aβ load) as well as across the whole brain [53], suggesting activated astrocytes in those locations. Other promising targets for imaging neuroinflammation that could be used to evaluate NDDs include cyclooxygenases [54,55,56,57], purinergic receptors [58], cannabinoid receptors [59, 60], colony stimulating factor receptor (CSF-1R) [61], inducible nitric oxide synthase (iNOS) [62], and triggering receptor expressed on myeloid cells 1 (TREM1) [63, 64].
References
Shah S, Sinharay S, Patel R, Solomon J, Lee JH, Schreiber-Stainthorp W, et al. PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections. Proc Natl Acad Sci U S A. 2022;119(15):e2110846119.
Hammoud DA, Sinharay S, Shah S, Schreiber-Stainthorp W, Maric D, Muthusamy S, et al. Neuroinflammatory changes in relation to cerebrospinal fluid viral load in simian immunodeficiency virus encephalitis. MBio. 2019;10(3):e00970.
Gong J, Szego ÉM, Leonov A, Benito E, Becker S, Fischer A, et al. Translocator protein ligand protects against neurodegeneration in the MPTP mouse model of parkinsonism. J Neurosci. 2019;39(19):3752–69.
Owen DR, Guo Q, Kalk NJ, Colasanti A, Kalogiannopoulou D, Dimber R, et al. Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study. J Cereb Blood Flow Metab. 2014;34(6):989–94.
Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab. 2013;33(1):53–8.
Fujita M, Kobayashi M, Ikawa M, Gunn RN, Rabiner EA, Owen DR, et al. Comparison of four (11)C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios. EJNMMI Res. 2017;7(1):84.
Lee JH, Simeon FG, Liow JS, Morse CL, Gladding RL, Montero Santamaria JA, et al. In vivo evaluation of six analogs of (11)C-ER176 as candidate (18)F-labeled radioligands for translocator protein 18 kDa (TSPO). J Nucl Med. 2022;63:1252.
Zhang HL, Wu J, Zhu J. The immune-modulatory role of apolipoprotein E with emphasis on multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Dev Immunol. 2010;2010:186813, 1.
Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358(9280):461–7.
Okello A, Edison P, Archer HA, Turkheimer FE, Kennedy J, Bullock R, et al. Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. Neurology. 2009;72(1):56–62.
Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, et al. Increased binding of peripheral benzodiazepine receptor in Alzheimer's disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry. 2008;64(10):835–41.
Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease. Brain. 2013;136(Pt 7):2228–38.
Gulyás B, Vas A, Tóth M, Takano A, Varrone A, Cselényi Z, et al. Age and disease related changes in the translocator protein (TSPO) system in the human brain: positron emission tomography measurements with [11C]vinpocetine. NeuroImage. 2011;56(3):1111–21.
Varrone A, Mattsson P, Forsberg A, Takano A, Nag S, Gulyás B, et al. 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. Eur J Nucl Med Mol Imaging. 2013;40(6):921–31.
Knezevic D, Mizrahi R. Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment. Prog Neuro-Psychopharmacol Biol Psychiatry. 2018;80(Pt B):123–31.
Parbo P, Ismail R, Sommerauer M, Stokholm MG, Hansen AK, Hansen KV, et al. Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study. Neurobiol Dis. 2018;117:211–6.
Toppala S, Ekblad LL, Tuisku J, Helin S, Johansson JJ, Laine H, et al. Association of Early β-amyloid accumulation and neuroinflammation measured with [(11)C]PBR28 in elderly individuals without dementia. Neurology. 2021;96(12):e1608–e19.
Cisbani G, Koppel A, Knezevic D, Suridjan I, Mizrahi R, Bazinet RP. Peripheral cytokine and fatty acid associations with neuroinflammation in AD and aMCI patients: an exploratory study. Brain Behav Immun. 2020;87:679–88.
Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer's disease. Brain. 2018;141(9):2740–54.
Klein J, Yan X, Johnson A, Tomljanovic Z, Zou J, Polly K, et al. Olfactory impairment is related to tau pathology and Neuroinflammation in Alzheimer's disease. J Alzheimers Dis. 2021;80(3):1051–65.
Malpetti M, Kievit RA, Passamonti L, Jones PS, Tsvetanov KA, Rittman T, et al. Microglial activation and tau burden predict cognitive decline in Alzheimer's disease. Brain. 2020;143(5):1588–602.
Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M, et al. Microglial activation and tau propagate jointly across braak stages. Nat Med. 2021;27(9):1592–9.
Passamonti L, Rodríguez PV, Hong YT, Allinson KSJ, Bevan-Jones WR, Williamson D, et al. [(11)C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy. Neurology. 2018;90(22):e1989–e96.
Terada T, Yokokura M, Obi T, Bunai T, Yoshikawa E, Ando I, et al. In vivo direct relation of tau pathology with neuroinflammation in early Alzheimer's disease. J Neurol. 2019;266(9):2186–96.
Zou J, Tao S, Johnson A, Tomljanovic Z, Polly K, Klein J, et al. Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment. Neurobiol Aging. 2020;85:11–21.
Yokokura M, Terada T, Bunai T, Nakaizumi K, Takebayashi K, Iwata Y, et al. Depiction of microglial activation in aging and dementia: positron emission tomography with [(11)C]DPA713 versus [(11)C](R)PK11195. J Cereb Blood Flow Metab. 2017;37(3):877–89.
Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A, et al. Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer's disease. J Nucl Med. 2008;49(8):1249–56.
Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW, et al. Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. J Nucl Med. 2015;56(5):701–6.
Bradburn S, Murgatroyd C, Ray N. Neuroinflammation in mild cognitive impairment and Alzheimer's disease: a meta-analysis. Ageing Res Rev. 2019;50:1–8.
Hamelin L, Lagarde J, Dorothée G, Potier MC, Corlier F, Kuhnast B, et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain. 2018;141(6):1855–70.
Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol. 2021;17(3):157–72.
Miguel-Álvarez M, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Garatachea N, et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect. Drugs Aging. 2015;32(2):139–47.
Howard R, Zubko O, Bradley R, Harper E, Pank L, O'Brien J, et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2020;77(2):164–74.
Lee J, Howard RS, Schneider LS. The current landscape of prevention trials in dementia. Neurotherapeutics. 2022;19(1):228–47.
Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nat Rev Immunol. 2022;1-17:657.
Lindqvist D, Kaufman E, Brundin L, Hall S, Surova Y, Hansson O. Non-motor symptoms in patients with Parkinson's disease—correlations with inflammatory cytokines in serum. PLoS One. 2012;7(10):e47387.
Warnecke T, Schäfer KH, Claus I, Del Tredici K, Jost WH. Gastrointestinal involvement in Parkinson's disease: pathophysiology, diagnosis, and management. NPJ Parkinsons Dis. 2022;8(1):31.
Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol Dis. 2006;21(2):404–12.
Ghadery C, Koshimori Y, Coakeley S, Harris M, Rusjan P, Kim J, et al. Microglial activation in Parkinson's disease using [(18)F]-FEPPA. J Neuroinflammation. 2017;14(1):8.
Ghadery C, Koshimori Y, Christopher L, Kim J, Rusjan P, Lang AE, et al. The interaction between neuroinflammation and β-amyloid in cognitive decline in Parkinson's disease. Mol Neurobiol. 2020;57(1):492–501.
Lavisse S, Goutal S, Wimberley C, Tonietto M, Bottlaender M, Gervais P, et al. Increased microglial activation in patients with Parkinson disease using [(18)F]-DPA714 TSPO PET imaging. Parkinsonism Relat Disord. 2021;82:29–36.
Varnäs K, Cselényi Z, Jucaite A, Halldin C, Svenningsson P, Farde L, et al. PET imaging of [(11)C]PBR28 in Parkinson's disease patients does not indicate increased binding to TSPO despite reduced dopamine transporter binding. Eur J Nucl Med Mol Imaging. 2019;46(2):367–75.
Zhang PF, Gao F. Neuroinflammation in Parkinson's disease: a meta-analysis of PET imaging studies. J Neurol. 2022;269(5):2304–14.
Laurell GL, Plavén-Sigray P, Jucaite A, Varrone A, Cosgrove KP, Svarer C, et al. Nondisplaceable binding is a potential confounding factor in (11)C-PBR28 translocator protein PET studies. J Nucl Med. 2021;62(3):412–7.
Lois C, González I, Izquierdo-García D, Zürcher NR, Wilkens P, Loggia ML, et al. Neuroinflammation in Huntington's disease: new insights with (11)C-PBR28 PET/MRI. ACS Chem Neurosci. 2018;9(11):2563–71.
Rocha NP, Charron O, Latham LB, Colpo GD, Zanotti-Fregonara P, Yu M, et al. Microglia activation in basal ganglia is a late event in Huntington disease pathophysiology. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e984.
Politis M, Lahiri N, Niccolini F, Su P, Wu K, Giannetti P, et al. Increased central microglial activation associated with peripheral cytokine levels in premanifest Huntington's disease gene carriers. Neurobiol Dis. 2015;83:115–21.
Gerhard A, Trender-Gerhard I, Turkheimer F, Quinn NP, Bhatia KP, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy. Mov Disord. 2006;21(1):89–93.
Palleis C, Sauerbeck J, Beyer L, Harris S, Schmitt J, Morenas-Rodriguez E, et al. In vivo assessment of neuroinflammation in 4-repeat tauopathies. Mov Disord. 2021;36(4):883–94.
Malpetti M, Passamonti L, Jones PS, Street D, Rittman T, Fryer TD, et al. Neuroinflammation predicts disease progression in progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 2021;92(7):769–75.
Gouilly D, Saint-Aubert L, Ribeiro MJ, Salabert AS, Tauber C, Péran P, et al. Neuroinflammation PET imaging of the translocator protein (TSPO) in Alzheimer's disease: an update. Eur J Neurosci. 2022;55(5):1322–43.
Janssen B, Vugts DJ, Windhorst AD, Mach RH. PET imaging of microglial activation-beyond targeting TSPO. Molecules. 2018;23(3):607.
Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, et al. Astrocyte reactivity with late-onset cognitive impairment assessed in vivo using (11)C-BU99008 PET and its relationship with amyloid load. Mol Psychiatry. 2021;26(10):5848–55.
Shukuri M, Mawatari A, Takatani S, Tahara T, Inoue M, Arakaki W, et al. Synthesis and preclinical evaluation of (18)F-labeled Ketoprofen methyl esters for Cyclooxygenase-1 imaging in neuroinflammation. J Nucl Med. 2022;63(11):1761.
Prabhakaran J, Molotkov A, Mintz A, Mann JJ. Progress in PET imaging of neuroinflammation targeting COX-2 enzyme. Molecules. 2021;26(11):3208.
Kumar JSD, Prabhakaran J, Molotkov A, Sattiraju A, Kim J, Doubrovin M, et al. Radiosynthesis and evaluation of [(18)F]FMTP, a COX-2 PET ligand. Pharmacol Rep. 2020;72(5):1433–40.
Kim MJ, Lee JH, Juarez Anaya F, Hong J, Miller W, Telu S, et al. First-in-human evaluation of [(11)C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain. Eur J Nucl Med Mol Imaging. 2020;47(13):3143–51.
Zheng QH. Radioligands targeting purinergic P2X7 receptor. Bioorg Med Chem Lett. 2020;30(12):127169.
Ahmad R, Postnov A, Bormans G, Versijpt J, Vandenbulcke M, Van Laere K. Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2016;43(12):2219–27.
Ahmad R, Koole M, Evens N, Serdons K, Verbruggen A, Bormans G, et al. Whole-body biodistribution and radiation dosimetry of the cannabinoid type 2 receptor ligand [11C]-NE40 in healthy subjects. Mol Imaging Biol. 2013;15(4):384–90.
Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc Natl Acad Sci U S A. 2019;116(5):1686–91.
Herrero P, Laforest R, Shoghi K, Zhou D, Ewald G, Pfeifer J, et al. Feasibility and dosimetry studies for 18F-NOS as a potential PET radiopharmaceutical for inducible nitric oxide synthase in humans. J Nucl Med. 2012;53(6):994–1001.
Lucot KL, Stevens MY, Bonham TA, Azevedo EC, Chaney AM, Webber ED, et al. Tracking innate immune activation in a MOUSE model of PARKINSON'S disease using TREM1 and TSPO pet tracers. J Nucl Med. 2022;63:1570.
Liu YS, Yan WJ, Tan CC, Li JQ, Xu W, Cao XP, et al. Common variant in TREM1 influencing brain amyloid deposition in mild cognitive impairment and Alzheimer's disease. Neurotox Res. 2020;37(3):661–8.
Janssen B, Mach RH. Development of brain PET imaging agents: strategies for imaging neuroinflammation in Alzheimer's disease. Prog Mol Biol Transl Sci. 2019;165:371–99.
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Hammoud, D.A., Herscovitch, P. (2023). Neuroinflammation Imaging in Neurodegenerative Diseases. In: Cross, D.J., Mosci, K., Minoshima, S. (eds) Molecular Imaging of Neurodegenerative Disorders. Springer, Cham. https://doi.org/10.1007/978-3-031-35098-6_9
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