PK11195 PET Research Articles

Prognostic value of neuroinflammation [11C]PK11195 PET on longitudinal cognitive decline and survival up to 15 years after PET in Alzheimer's disease

AbstractBackgroundNeuroinflammation plays a key role in Alzheimer’s disease (AD) pathophysiology. However, whether neuroinflammation has a prognostic effect on disease progression is largely unknown. Therefore, we aim to investigate the role of neuroinflammation as measured using PET on longitudinal cognition and survival.MethodWe included 29 amyloid‐positive participants (N=10 MCI, N=19 AD dementia) from a historical cohort who underwent dynamic [11C]PK11195 (TSPO) PET to quantify neuroinflammation (Table 1). [11C]PK11195 BPND was obtained using supervised cluster analysis and quantified in the parietal and temporal cortex. [11C]PK11195 BPND values were z‐scored to young healthy controls (N=12). Longitudinal MMSE covering a period up to 11 years was used to measure cognitive decline (median: 3.9, range: 0.3‐11.6 years). We used linear mixed models with random intercept and slope corrected for age, sex and education to investigate the effect of neuroinflammation on cognition. Survival data were available for all participants, up to 15.7 years after PET. To examine the influence of neuroinflammation on survival time, we used age, sex, and diagnosis adjusted cox proportional‐hazards models for both regions.ResultDemographic characteristics and mean [11C]PK11195 BPND can be found in table 1. Overall, the group showed a mean annualized decline of ‐1.86±1.42 points on MMSE and had a median survival time of 7.6 years (range: 0.4‐15.7) after PET. Temporal or parietal [11C]PK11195 BPND did not predict longitudinal MMSE (parietal: β=0.15, p=0.438; temporal: β=‐0.11, p=0.660) (Figure 1). Higher parietal [11C]PK11195 BPND was marginally associated with shorter survival (HR = ‐0.39, P=0.043) (Figure 2A). There was no significant difference in survival time with higher temporal [11C]PK11195 BPND (HR= ‐0.42, P=0.053) (Figure 2B).ConclusionIn this initial set of analyses covering up to 11 years of cognitive follow‐up and survival information of 15 years after PET, we found preliminary evidence of a shorter survival with increasing parietal neuroinflammation, but no associations between neuroinflammation PET and the rate of cognitive decline. Future research could explore the effect of neuroinflammation PET on more specific cognitive domains and biological measures such as cortical thickness.

Physical exercise prevents age‐related changes in [11C]PK11195 uptake in a mouse model of Down Syndrome

AbstractBackgroundDown syndrome (DS) is associated with mitochondrial dysfunction leading to higher levels of oxidative stress and cell degeneration. This fact, together with the overexpression of AD‐related genes in trisomy 21, increases the risk of developing Alzheimer's disease (AD). Thus, it is important to look for interventions that could prevent mitochondrial damage before symptoms occur. Physical activity is a non‐pharmacological intervention that provides an anti‐inflammatory response and increases the levels of neurotrophic factors that are beneficial for brain health. Therefore, the aim of this study is to evaluate the effect of physical activity on microglial function during the aging process in a transgenic mouse model of DS using [11C]PK11195 positron emission tomography.MethodTs65Dn male and female mice (euploid and trisomic) were used in this study (CEUA 1292/2019). Animals were subjected to physical activity on a treadmill from 2 to 20 months of age, 3 times per week. [11C]PK11195 PET images were acquired at 5, 14, and 20 months of age. For image acquisition, animals were injected intravenously with [11C]PK11195. Images were acquired in a small animal PET scanner 30 min after tracer injection, and acquisition took 20 min, with animals kept under anesthesia throughout the acquisition. PET images were co‐registered to a T2‐MRI template and the standardized uptake value (SUV) was calculated in the whole brain.ResultThroughout the aging process, a decrease in the [11C]PK11195 uptake was observed in the trisomic animals at 20 months of age, when compared to the age of 5 months (‐60.7%, 0.56±0.13 vs. 0.22±0.1, p<0.05); and 14 months (‐55.1%, 0.49±0.09 vs. 0.22±0.1, p<0.01). However, the exercised trisomic animals did not present a decrease in the [11C]PK11195 uptake at 20 months being comparable (no statistical differences) to the euploid animals (exercise and non‐exercise groups).ConclusionOur data suggest that physical activity could prevent a possible deleterious effect of accelerated aging in mitochondrial function, in the presence of the trisomy 21, since lower [11C]PK11195 uptake could be associated with mitochondrial dysfunction and reduced expression of the TSPO protein.

Neuroinflammation and blood-brain barrier breakdown in acute, clinical intracerebral hemorrhage

Neuroinflammation is a promising therapeutic target in intracerebral hemorrhage (ICH), characterized in the brain by microglial activation and blood-brain barrier (BBB) breakdown. In this study, 36 acute, spontaneous, supratentorial ICH patients underwent dynamic contrast-enhanced MRI to measure BBB permeability (Ktrans) 1–3 days post-onset and 16 returned for [11C](R)-PK11195 PET to quantify microglial activation (BPND), 2–7 days post-onset. We first tested if these markers were increased and co-localized in the perihematomal brain and found that perihematomal Ktrans and BPND were increased vs. the contralateral brain, but regions of high Ktrans and BPND only overlapped by a mean of 4.9%. We then tested for associations of perihematomal Ktrans and BPND with clinical characteristics (age, ICH volume & location, blood pressure), other markers of inflammation (edema, IL-6, and CRP), and long-term functional outcome (90-day mRS). Lower perihematomal BPND was associated with increasing age. Lobar hemorrhage was associated with greater Ktrans than deep, but Ktrans and BPND were not associated with ICH volume, or other inflammatory markers. While perihematomal Ktrans and BPND were not associated with outcome, contralateral Ktrans was significantly associated with greater 90-day mRS. Exploratory analyses demonstrated that blood pressure variability over 72 h was also associated with contralateral Ktrans.

[123I]CLINDE SPECT as a neuroinflammation imaging approach in a rat model of stroke

Poststroke neuroinflammation exacerbates disease progression. [11C]PK11195-positron emission tomography (PET) imaging has been used to visualize neuroinflammation; however, its short half-life of 20min limits its clinical use. [123I]CLINDE has a longer half-life (13h); therefore, [123I]CLINDE-single-photon emission computed tomography (SPECT) imaging is potentially more practical than [11C]PK11195-PET imaging in clinical settings. The objectives of this study were to 1) validate neuroinflammation imaging using [123I]CLINDE and 2) investigate the mechanisms underlying stroke in association with neuroinflammation using multimodal techniques, including magnetic resonance imaging (MRI), gas-PET, and histological analysis, in a rat model of ischemic stroke, that is, permanent middle cerebral artery occlusion (pMCAo). At 6days post-pMCAo, [123I]CLINDE-SPECT considerably corresponded to the immunohistochemical images stained with the CD68 antibody (a marker for microglia/microphages), comparable to the level observed in [11C]PK11195-PET images. In addition, the [123I]CLINDE-SPECT images corresponded well with autoradiography images. Rats with severe infarcts, as defined by MRI, exhibited marked neuroinflammation in the peri-infarct area and less neuroinflammation in the ischemic core, accompanied by a substantial reduction in the cerebral metabolic rate of oxygen (CMRO2) in 15O-gas-PET. Rats with moderate-to-mild infarcts exhibited neuroinflammation in the ischemic core, where CMRO2 levels were mildly reduced. This study demonstrates that [123I]CLINDE-SPECT imaging is suitable for neuroinflammation imaging and that the distribution of neuroinflammation varies depending on the severity of infarction.

Sex-driven variability in TSPO-expressing microglia in MS patients and healthy individuals.

Males with multiple sclerosis (MS) have a higher risk for disability progression than females, but the reasons for this are unclear. We hypothesized that potential differences in TSPO-expressing microglia between female and male MS patients could contribute to sex differences in clinical disease progression. The study cohort consisted of 102 MS patients (mean (SD) age 45.3 (9.7) years, median (IQR) disease duration 12.1 (7.0-17.2) years, 72% females, 74% relapsing-remitting MS) and 76 age- and sex-matched healthy controls. TSPO-expressing microglia were measured using the TSPO-binding radioligand [11C](R)-PK11195 and brain positron emission tomography (PET). TSPO-binding was quantified as distribution volume ratio (DVR) in normal-appearing white matter (NAWM), thalamus, whole brain and cortical gray matter (cGM). Male MS patients had higher DVRs compared to female patients in the whole brain [1.22 (0.04) vs. 1.20 (0.02), p = 0.002], NAWM [1.24 (0.06) vs. 1.21 (0.05), p = 0.006], thalamus [1.37 (0.08) vs. 1.32 (0.02), p = 0.008] and cGM [1.25 (0.04) vs. 1.23 (0.04), p = 0.028]. Similarly, healthy men had higher DVRs compared to healthy women except for cGM. Of the studied subgroups, secondary progressive male MS patients had the highest DVRs in all regions, while female controls had the lowest DVRs. We observed higher TSPO-binding in males compared to females among people with MS and in healthy individuals. This sex-driven inherent variability in TSPO-expressing microglia may predispose male MS patients to greater likelihood of disease progression.

Evaluation of Non-Invasive Methods for (R)-[11C]PK11195 PET Image Quantification in Multiple Sclerosis.

This study aims to evaluate non-invasive PET quantification methods for (R)-[11C]PK11195 uptake measurement in multiple sclerosis (MS) patients and healthy controls (HC) in comparison with arterial input function (AIF) using dynamic (R)-[11C]PK11195 PET and magnetic resonance images. The total volume of distribution (VT) and distribution volume ratio (DVR) were measured in the gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, cerebellum, and brainstem using AIF, the image-derived input function (IDIF) from the carotid arteries, and pseudo-reference regions from supervised clustering analysis (SVCA). Uptake differences between MS and HC groups were tested using statistical tests adjusted for age and sex, and correlations between the results from the different quantification methods were also analyzed. Significant DVR differences were observed in the gray matter, white matter, putamen, pallidum, thalamus, and brainstem of MS patients when compared to the HC group. Also, strong correlations were found in DVR values between non-invasive methods and AIF (0.928 for IDIF and 0.975 for SVCA, p < 0.0001). On the other hand, (R)-[11C]PK11195 uptake could not be differentiated between MS patients and HC using VT values, and a weak correlation (0.356, p < 0.0001) was found between VTAIF and VTIDIF. Our study shows that the best alternative for AIF is using SVCA for reference region modeling, in addition to a cautious and appropriate methodology.

Peripheral and central markers of inflammation increased in frontotemporal dementia and related conditions

AbstractBackgroundNeuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET).MethodBlood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND.ResultSixteen cytokines were undetectable in &gt;50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2).ConclusionThis data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies.

Peripheral and central markers of inflammation increased in frontotemporal dementia and related conditions

AbstractBackgroundNeuroinflammation is an important pathogenic mechanism in frontotemporal dementia (FTD) and related disorders. Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, and as proportionate to symptom severity and rate of progression. However, data on inflammation blood markers of inflammation and their relationship with central inflammation are limited. Here we assess inflammatory patterns of 41 serum cytokines from patients with FTD and related conditions, and their association with regional microglial activation (TSPO PET).MethodBlood samples were obtained from 29 healthy controls, and 214 patients with a clinical diagnosis of behavioural variant FTD (bvFTD = 52), primary progressive aphasia (PPA = 51), progressive supranuclear palsy (PSP = 58) and corticobasal syndrome (CBS = 53). Serum assays used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to reduce dimensionality of cytokine data. A sub‐group of patients (bvFTD = 10, PPA = 17, PSP = 17) underwent PET imaging with [11C]PK11195 PET, as index of microglial activation. Kruskal‐Wallis and pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls. [11C]PK11195 non‐displaceable binding potential (BPND) was calculated in 83 regions of interest (ROIs) across the whole brain. Spearman correlations tested associations between cytokine components and regional [11C]PK11195 BPND.ResultSixteen cytokines were undetectable in &gt;50% of participants and thus excluded. The first component identified by the PCA on the remaining 25 cytokines (explaining 19.7%) was strongly loaded by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on detected significant differences across the groups (χ2(4) = 11.0, p = 0.027), and the pairwise t‐tests identified significant differences between each patient cohort and controls (Figure 1, right). Spearman correlations identified regional positive associations between individual cytokine‐component scores and microglial activation in frontal and brainstem regions across the whole group (R≥0.25), and syndrome‐specific regional patterns (Figure 2).ConclusionThis data‐driven approach identified a pro‐inflammatory profile across FTD and related conditions, which is positively associated with higher levels of microglial activation in syndrome‐related key brain regions. Blood‐based tests could greatly increase the scalability and access to neuroinflammatory assessment in dementia and experimental medicine studies.

Amyloid deposition and neuroinflammation in middle‐aged to older individuals with Down syndrome: a PET evaluation

AbstractBackgroundDown syndrome (DS) is characterized by trisomy for chromosome 21 and presents a high incidence and early development of Alzheimer’s disease (AD) (Ram G et al. 2011). The current study aims to evaluate the presence of amyloid in people with DS in different age spans and its correlation with neuroinflammation.MethodIndividuals with DS aged 20‐34 (n = 8), 35‐49 (n = 8), ≥ 50 (n = 4), and cognitively normal individuals without DS (controls n = 11) were evaluated with [11C]PK11195 PET imaging (neuroinflammation) and [11C]PIB PET (β‐amyloid) in a hybrid PET/MRI equipment. The radiopharmaceuticals were administered intravenously (∼370 MBq), and the images were acquired dynamically during 60 min ([11C]PK11195) and 70 min ([11C]PIB). PET images were quantified in the PMOD™ v4.1 software and the results were presented in SUV (Standardized Uptake Value) for [11C]PK11195 and SUVratio with the cerebellum crus as a reference region for [11C]PIB. [11C]PIB images were also visually classified as amyloid positive or negative by an experienced nuclear physician. Statistical analysis was performed by one‐way ANOVA and Bonferroni posthoc, and the differences were considered significant when P≤0.05.ResultAll individuals with DS ≥50 years were amyloid positive and showed increased [11C]PK11195 uptake when compared to younger DS subjects and the control group. Differences were seen particularly in the ≥50 group in the following areas: a) posterior cingulate (1.32±0.05, vs. control = 0.71±0.13, p&lt;0.0001; vs. 20‐34 group = 0.67±0.16, p&lt;0.0001; and 35‐49 group = 0.75±0.14; p = 0.0003); b) amygdala (0.86±0.14, vs. control = 0.62±0.10, p = 0.0450; vs. 20‐34 group = 0.57±0.09, p = 0.0114); c) caudate (0.70±0.12, vs. 20‐34 group = 0.47±0.10, p = 0.0195); d) and thalamus (0.90±0.11, vs. the 20‐34 group = 0.62±0.11, p = 0.0171). [11C]PIB uptake in the posterior cingulate correlated with [11C]PK11195 uptake (r = 0.6201; p = 0.006) in individuals with DS across all age spans.ConclusionThe increased uptake of [11C]PK11195 in subjects with DS≥ 50 years indicates the presence of a neuroinflammatory process in different brain areas that may be associated with β‐amyloid plaque deposition early in the aging process.

Lithium carbonate treatment decrease neuroinflammation and ameliorates long‐term memory in a Down syndrome animal model

AbstractBackgroundIndividuals with Down Syndrome (DS) have an increased genetic risk for developing Alzheimer’s Disease (AD), due to a higher expression of genes related to the pathophysiological development of the disease and to the inflammatory process. Brain damage is already substantial when the first clinical signs of AD appear, it is essential to study therapeutic alternatives that delay its development. As lithium carbonate has been identified as a neuroprotective and neuroplastic agent in neurodegeneration, the aim of this study is to evaluate the treatment effect of lithium carbonate in the neuroinflammation and long‐term memory of Ts65Dn animal model of DS.MethodTs65Dn mice (trisomy confirmed by genotyping) were treated with a lithium carbonate microdose (0.25 mg/kg dissolved in water) for 18 months and compared to non‐treated animals. To evaluate the treatment, [11C]PK11195 PET images were acquired at the ages of 5, 14, 20 and 24 months. Whole brain images were quantified in SUV (Standardized Uptake Value) and long‐term memory was assessed by the novel object recognition test (1).Result[11C]PK11195 uptake was increased at 14 months in the non‐treated animals when compared to the respective age of 5 months (+29%), although not statistically significant. However, when mice were treated with lithium, this increase was not detected. Compared to 14 months, at the ages of 20 and 24 months, there was a decreased uptake in the non‐treated animals (Ts65Dn: ‐52%, p = 0.01 at 20 months; Ts65Dn: ‐59%, p = 0.006; at 24 months) and whereas in Ts65Dn‐lithium, the uptake did not change significantly among the ages. There was a decrease in the long‐term memory index in the non‐treated animals, at the ages of 20 (p = 0.03) and 24 months (p = 0.009), compared to 14 months‐old whereas in the treated animals the memory was preserved.ConclusionThe treatment with lithium carbonate prevented glial cells alterations during life‐span and preserved long‐term memory of a Down syndrome animal model indicating that this treatment can contribute to a healthy brain aging in this syndrome.

P15.10.A USE OF DUAL TRACERS PET AS A PREDICTIVE BIOMARKER OF THE SITE OF RECURRENCE IN HIGH GRADE GLIOMA

Abstract BACKGROUND High grade glioma has poor survival rate and tumour recurrence occurs despite current treatments. Positron emission tomography (PET) with [11C](R)PK11195 can evaluate translocator protein (TSPO) and [11C]methionine can assess amino acid transport. PET imaging might have the potential to detect tumour regions at baseline that will later develop as the site of recurrence. We compare TSPO measured using [11C](R)PK11195 and amino acid transport using [11C]methionine at baseline and investigate to what extend the two tracers can predict the site of tumour recurrence. MATERIAL AND METHODS Twelve patients with newly diagnosed high grade glioma underwent multimodal imaging studies. Preoperative MRI, [11C](R)PK11195 PET, [11C]methionine PET and postoperative (follow-up) MRI were co-registered. [11C](R)PK11195 binding potential (BPND) maps were generated using the simplified reference tissue model with grey matter cerebellar time-activity curve as tissue input function. [11C]methionine uptake was calculated as tumour to background ratio (TBR). Contrast enhancing volumes of interest (VOI) were defined on T1W post contrast. The VOI of [11C]methionine high uptake was standardized as TBR&amp;gt;1.7. For [11C](R)PK11195 VOI, the mean BPND + SD of grey matter voxels was calculated from individual maps of healthy control (HC; n = 50). Afterward, 95% confidence interval threshold (HC mean + 1.96 × SD) was used to describe high voxel activity in tumour (BPND&amp;gt;0.35). Tumour recurrence VOI was defined as contrast enhancement on the follow-up images. RESULTS The mean percentage overlap between high [11C](R)PK11195 BPND and [11C]methionine uptake was 48±17%. The mean percentage of each VOI showing exclusively high [11C](R)PK11195 BPND or exclusively high [11C]methionine was 25±21 or 27±22 respectively. The mean percentage overlap between high [11C](R)PK11195 and contrast enhancement is 36±14. The mean percentage of exclusively hight [11C](R)PK11195 or exclusively contrast enhancement were 38±18 or 26±25 respectively. The mean percentage overlap between high [11C]methionine and contrast enhancement were 47±12. The mean percentage of exclusively [11C]methionine or contrast enhancement were 36±20 or 17±17 respectively. The percentage volume overlap between contrast enhancing regions at recurrence and baseline [11C](R)PK11195 or [11C]methionine was 20±13 or 25±13 respectively. CONCLUSION The two PET tracers have high overlap although some regions are specific for high TSPO binding without high methionine uptake which could reflect an inflammatory component within the tumour microenvironment. The common regions between methionine and contrast enhancement is larger than TSPO binding which could represent that TSPO binding is less effected by disrupted blood-brain barrier. The mean percentage overlap with VOI representing tumour recurrence were similar.

18F]FDG and [11C]PK11195 PET imaging in the evaluation of brown adipose tissue - effects of cold and pharmacological stimuli and their association with crotamine intake in a male mouse model

Male C57BL/6 mice were studied with the glucose analogue [18F]FDG (n=21) and the TSPO mitochondrial tracer [11C]PK11195 (n=28), without stimulus and after cold (6-9°C) or beta-agonist (CL316243) stimuli. PET studies were performed at baseline and after 21days of daily treatment with crotamine, which is a peptide described to induce adipocyte tissue browning and to increase BAT metabolism. Tracer uptake (SUVmax) was measured in the interscapular BAT and translocator protein 18kDa (TSPO) expression was evaluated by immunohistochemistry. The cold stimulus increased [18F]FDG uptake compared to no-stimulus (5.21±1.05 vs. 2.03±0.21, p<0.0001) and to beta-agonist stimulus (2.65±0.39, p=0.0003). After 21days of treatment with crotamine, there was no significant difference in the [18F]FDG uptake compared to the baseline in the no-stimulus group and in the cold-stimulus group, with a significant increase in uptake after CL stimulus (baseline: 2.65±0.39; 21days crotamine: 4.77±0.81, p=0.0003). Evaluation of [11C]PK11195 at baseline shows that CL stimulus increases the BAT uptake compared to no-stimulus (4.47±0.66 vs. 3.36±0.68, p=0.014). After 21days of treatment with crotamine, there was no significant difference in the [11C]PK11195 uptake compared to the baseline in the no-stimulus group (2.94±0.58, p=0.7864) and also after CL stimulus (3.55±0.79, p=0.085). TSPO expression correlated with [11C]PK11195 uptake (r=0.83, p=0.018) but not with [18F]FDG uptake (r=0.40, p=0.516). [11C]PK11195 allowed the identification of BAT under thermoneutral conditions or after beta3-adrenergic stimulation in a direct correlation with TSPO expression. The beta-adrenergic stimulus, despite presenting a lower intensity of glycolytic activation compared to cold at baseline, allowed the observation of an increase in BAT uptake of [18F]FDG after 21days of crotamine administration. Although some limitations were observed for the metabolic changes induced by crotamine, this study reinforced the potential of using [11C]PK11195 and/or [18F]FDG-PET to monitor the activation of BAT.

Textural properties of microglial activation in Alzheimer's disease as measured by (R)-[11C]PK11195 PET.

Alzheimer's disease is the most common form of dementia worldwide, accounting for 60-70% of diagnosed cases. According to the current understanding of molecular pathogenesis, the main hallmarks of this disease are the abnormal accumulation of amyloid plaques and neurofibrillary tangles. Therefore, biomarkers reflecting these underlying biological mechanisms are recognized as valid tools for an early diagnosis of Alzheimer's disease. Inflammatory mechanisms, such as microglial activation, are known to be involved in Alzheimer's disease onset and progression. This activated state of the microglia is associated with increased expression of the translocator protein 18 kDa. On that account, PET tracers capable of measuring this signature, such as (R)-[11C]PK11195, might be instrumental in assessing the state and evolution of Alzheimer's disease. This study aims to investigate the potential of Gray Level Co-occurrence Matrix-based textural parameters as an alternative to conventional quantification using kinetic models in (R)-[11C]PK11195 PET images. To achieve this goal, kinetic and textural parameters were computed on (R)-[11C]PK11195 PET images of 19 patients with an early diagnosis of Alzheimer's disease and 21 healthy controls and submitted separately to classification using a linear support vector machine. The classifier built using the textural parameters showed no inferior performance compared to the classical kinetic approach, yielding a slightly larger classification accuracy (accuracy of 0.7000, sensitivity of 0.6957, specificity of 0.7059 and balanced accuracy of 0.6967). In conclusion, our results support the notion that textural parameters may be an alternative to conventional quantification using kinetic models in (R)-[11C]PK11195 PET images. The proposed quantification method makes it possible to use simpler scanning procedures, which increase patient comfort and convenience. We further speculate that textural parameters may also provide an alternative to kinetic analysis in (R)-[11C]PK11195 PET neuroimaging studies involving other neurodegenerative disorders. Finally, we recognize that the potential role of this tracer is not in diagnosis but rather in the assessment and progression of the diffuse and dynamic distribution of inflammatory cell density in this disorder as a promising therapeutic target.

Central metabolites and peripheral parameters associated neuroinflammation in fibromyalgia patients: A preliminary study.

To identify central metabolites and peripheral measures associated with neuroinflammation in fibromyalgia (FM), we scanned [11C]-(R)-PK11195 positron emission tomography and magnetic resonance spectroscopy in FM patients. We measured associations between neurometabolite levels measured by magnetic resonance spectroscopy and the extent of neuroinflammation inferred by the distribution volume ratios of [11C]-(R)-PK11195 positron emission tomography in 12 FM patients and 13 healthy controls. We also examined the associations between peripheral parameters, such as creatinine and C-reactive protein, and neuroinflammation. In FM patients, we found negative correlations between neuroinflammation and the creatine (Cr)/total creatine (tCr; Cr + phosphocreatine) ratios in the right (r = -0.708, P = .015) and left thalamus (r = -0.718, P = .008). In FM patients, negative correlations were apparent between neuroinflammation and the glutamate/tCr ratio in the right insula (r = -0.746, P = .005). In FM patients, we found negative correlations between neuroinflammation in the left thalamus (r = -0.601, P = .039) and left insula (r = -0.598, P = .040) and the blood creatinine levels. Additionally, we found significant correlations of other peripheral measures with neuroinflammation in FM patients. Our results suggest that both central metabolites, such as Cr and glutamate, and peripheral creatinine and other parameters are associated with neuroinflammation in patients with FM.

The effect of the tumour necrosis factor-alpha-inhibitor etanercept on microglial activation patients with mild cognitive impairment—a PET study

Aim: Microglial activation is increasingly recognised as a factor in the progression of Alzheimer’s disease (AD) and may be modified by systemic inflammatory signals including serum tumour necrosis factor (TNF)-α. The aim was to investigate whether blockade of peripheral TNF-α with peripheral inhibitors such as etanercept reduces microglial activation in prodromal AD. Methods: A one-year, multi-centre, phase 2, double-blind randomised placebo-controlled trial (RPCT) was performed, to assess the effect of weekly 50 mg s.c. etanercept in amyloid positive mild cognitive impaired participants on the change in microglial activation as measured by [11C](R)-PK11195 positron emission tomography (PET). Secondary objectives were to ascertain the change in cortical amyloid load on PET and the change in the Montreal Cognitive Assessment (MoCA). Results: Forty-four subjects consented to the study. Twenty-eight subjects failed screening including six subjects who were amyloid negative on visual read of the AmyvidTM PET scans. Thirteen of sixteen subjects with mild cognitive impairment (MCI) due to AD completed the baseline [11C](R)-PK11195 PET scan and were randomised to either placebo or etanercept. Three patients who consented were not able to complete screening due to early termination of the study following delays in study commencement. [11C](R)-PK11195 binding potential (BP) at baseline showed an almost global increase in MCI patients as compared to age-matched controls. Compliance to medication was high over the twelve-month trial period with etanercept being well tolerated. The study did not achieve statistical power to show a significant effect of etanercept over 52 weeks in the limited number of patients with MCI on microglial activation as measured by [11C](R)-PK11195 PET. Overall uptake of florbetapir in the follow up (FU) scans remained stable. The study was not powered to show statistical differences in psychometric ratings between groups. Conclusions: This study did not show evidence that treatment with etanercept over one year would modulate microglial activation in amyloid positive MCI patients (EudraCT identifier: 2015-002145-63, https://www.clinicaltrialsregister.eu; International Standard Randomised Controlled Trial Number identifier: ISRCTN12472821, https://www.isrctn.com).

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy, and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesised that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multi-modal imaging assessment, including [11C]PK11195 positron emission tomography (PET) to index microglial activation, and structural magnetic resonance imaging (MRI) to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, ten the semantic variant of primary progressive aphasia and ten had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination (ACE-R), at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (-0.70, p=0.01), but not for grey-matter volumes (p>0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Prone position decreases acute lung inflammation measured by [11C](R)-PK11195 positron emission tomography in experimental acute respiratory distress syndrome.

Whether prone positioning (PP) modulates acute lung inflammation by the modulation of biomechanical forces of ventilator-induced lung injuries (VILIs) remains unclear. We aimed to demonstrate that PP decreases acute lung inflammation in animals with experimental acute respiratory distress syndrome (ARDS). Animals were under general anesthesia and protective ventilation (tidal volume 6 mL·kg-1, PEEP 5 cmH2O). ARDS was induced by intratracheal instillation of chlorohydric acid. Animals were then randomized to PP, or to supine position (SP). After 4 h, a positron emission tomography (PET) acquisition with [11C](R)-PK11195 was performed coupled with computerized tomography (CT) acquisitions, allowing the CT quantification of VILI-associated parameters. [11C](R)-PK11195 lung uptake was quantified using pharmacokinetic multicompartment models. Analyses were performed on eight lung sections distributed along the antero-posterior dimension. Six animals were randomized to PP, five to SP (median [Formula: see text]/[Formula: see text] [interquartile range]: 164 [102-269] mmHg). The normally aerated compartment was significantly redistributed to the posterior lung regions of animals in PP, compared with SP. Dynamic strain was significantly increased in posterior regions of SP animals, compared with PP. After 4 h, animals in PP had a significantly lower uptake of [11C](R)-PK11195, compared with SP. [11C](R)-PK11195 regional uptake was independently associated with the study group, dynamic strain, tidal hyperinflation, and regional respiratory system compliance in multivariate analysis. In an experimental model of ARDS, 4 h of PP significantly decreased acute lung inflammation assessed with PET. The beneficial impact of PP on acute lung inflammation was consecutive to the combination of decreased biomechanical forces and changes in the respiratory system mechanics.NEW & NOTEWORTHY Prone position decreases acute lung macrophage inflammation quantified in vivo with [11C](R)-PK11195 positron emission tomography in an experimental acute respiratory distress syndrome. Regional macrophage inflammation is maximal in the most anterior and posterior lung section of supine animals, in relation with increased regional tidal strain and hyperinflation, and reduced regional lung compliance.

Evaluation of (R)-[11C]PK11195 PET/MRI for Spinal Cord-Related Neuropathic Pain in Patients with Cervical Spinal Disorders

Activated microglia are involved in secondary injury after acute spinal cord injury (SCI) and in development of spinal cord-related neuropathic pain (NeP). The aim of the study was to assess expression of translocator protein 18 kDa (TSPO) as an indicator of microglial activation and to investigate visualization of the dynamics of activated microglia in the injured spinal cord using PET imaging with (R)-[11C]PK11195, a specific ligand for TSPO. In SCI chimeric animal models, TSPO was expressed mainly in activated microglia. Accumulation of (R)-[3H]PK11195 was confirmed in autoradiography and its dynamics in the injured spinal cord were visualized by (R)-[11C]PK11195 PET imaging in the acute phase after SCI. In clinical application of (R)-[11C]PK11195 PET/MRI of the cervical spinal cord in patients with NeP related to cervical disorders, uptake was found in cases up to 10 months after injury or surgery. No uptake could be visualized in the injured spinal cord in patients with chronic NeP at more than 1 year after injury or surgery, regardless of the degree of NeP. However, a positive correlation was found between standardized uptake value ratio and the severity of NeP, suggesting the potential of clinical application for objective evaluation of chronic NeP.

Potential of [11C](R)-PK11195 PET Imaging for Evaluating Tumor Inflammation: A Murine Mammary Tumor Model.

Breast tumor inflammation is an immunological process that occurs mainly by mediation of Tumor-Associated Macrophages (TAM). Aiming for a specific measurement of tumor inflammation, the current study evaluated the potential of Positron Emission Tomography (PET) imaging with [11C](R)-PK11195 to evaluate tumor inflammation in a mammary tumor animal model. Female Balb/C mice were inoculated with 4T1 cells. The PET imaging with [11C](R)-PK11195 and [18F]FDG was acquired 3 days, 1 week, and 2 weeks after cell inoculation. The [11C](R)-PK11195 tumor uptake increased from 3 days to 1 week, and decreased at 2 weeks after cell inoculation, as opposed to the [18F]FDG uptake, which showed a slight decrease in uptake at 1 week and increased uptake at 2 weeks. In the control group, no significant differences occurred in tracer uptake over time. Tumor uptake of both radiopharmaceuticals is more expressed in tumor edge regions, with greater intensity at 2 weeks, as demonstrated by [11C](R)-PK11195 autoradiography and immunofluorescence with TSPO antibodies and CD86 pro-inflammatory phenotype. The [11C](R)-PK11195 was able to identify heterogeneous tumor inflammation in a murine model of breast cancer and the uptake varied according to tumor size. Together with the glycolytic marker [18F]FDG, molecular imaging with [11C](R)-PK11195 may provide a better characterization of inflammatory responses in cancer.

In vivo molecular imaging of the neuroinflammatory response to peripheral acute bacterial infection in older patients with cognitive dysfunction: A cross-sectional controlled study

IntroductionChronic neuroinflammatory events have been implicated in the pathophysiology of neurodegenerative conditions but no studies have directly examined the neuroinflammatory response to acute systemic infection in older people with dementia. The objective of this study was to determine the magnitude of the neuroinflammatory response triggered by acute systemic infection in older subjects with dementia and/or delirium compared to cognitively healthy controls.MethodsWe recruited 19 participants (4 with delirium, 4 with dementia, 4 with delirium superimposed on dementia, 7 cognitively healthy) hospitalized with acute systemic bacterial infection not involving the Central Nervous System. Participants underwent [11C]-PK11195 PET and a neuropsychological assessment during hospital stay. The distribution volume ratio was estimated in the regions-of-interest using the Hammers’ brain atlas.ResultsIn the subcortical analysis, we found that the cognitively healthy group presented regions with significantly higher DVR intensity than the other groups in the choroid plexus. Mean choroid plexus DVR positively correlated with MoCA (r = 0.66, p = 0.036).ConclusionThis study suggests that dementia and/or delirium is associated with a reduced neuroinflammatory response to acute systemic bacterial infection which can be the result of an immunosuppressive brain environment.