Insights into disseminated MS brain pathology with multimodal diffusion tensor and PET imaging

ObjectiveTo evaluate in vivo the co-occurrence of microglial activation and microstructural white matter (WM) damage in the MS brain and to examine their association with clinical disability.Methods18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI (cMRI) were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial, and radial (RD) diffusivities were calculated within the whole normal-appearing WM (NAWM) and segmented NAWM regions appearing normal in cMRI. Fifty-five patients with MS and 15 healthy controls (HCs) were examined.ResultsMicrostructural damage was observed in the NAWM of the MS brain. DTI parameters of patients with MS were significantly altered in the NAWM compared with an age- and sex-matched HC group: mean FA was decreased, and MD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p < 0.05 for all correlations; p < 0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with the Expanded Disability Status Scale score.ConclusionsWidespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI allow in vivo evaluation of widespread MS pathology not visible using cMRI.

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Insights into smouldering MS brain pathology with multimodal diffusion tensor and PET imaging

10.1101/2020.01.09.20017012 ◽

2020 ◽

Author(s):

Svetlana Bezukladova ◽

Jouni Tuisku ◽

Markus Matilainen ◽

Anna Vuorimaa ◽

Marjo Nylund ◽

...

Keyword(s):

White Matter ◽

Pet Imaging ◽

Microglial Activation ◽

Diffusion Tensor ◽

Volume Ratio ◽

Translocator Protein ◽

Control Group ◽

In Vivo Evaluation ◽

Conventional Mri

Objective: To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter damage in multiple sclerosis (MS) brain, and to examine their association with clinical disability. Methods: 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO-binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the whole normal appearing white matter (NAWM) and segmented NAWM regions appearing normal in conventional MRI. 55 MS patients and 15 healthy controls were examined. Results: Microstructural damage was observed in the NAWM of MS brain. DTI parameters of MS patients were significantly altered in the NAWM, when compared to an age- and sex-matched healthy control group: mean FA was decreased, and MD, AD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p<0.05 for all correlations; p<0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with expanded disability status scale (EDSS). Conclusions: Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI imaging allows in vivo evaluation of widespread MS pathology not visible using conventional MRI.

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Natalizumab treatment reduces microglial activation in the white matter of the MS brain

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000574 ◽

2019 ◽

Vol 6 (4) ◽

pp. e574 ◽

Cited By ~ 9

Author(s):

Marcus Sucksdorff ◽

Jouni Tuisku ◽

Markus Matilainen ◽

Anna Vuorimaa ◽

Sarah Smith ◽

...

Keyword(s):

White Matter ◽

Gray Matter ◽

Pet Imaging ◽

Microglial Activation ◽

Volume Ratio ◽

Translocator Protein ◽

Cns Inflammation ◽

Normal Appearing White Matter ◽

Natalizumab Treatment

ObjectiveTo evaluate whether natalizumab treatment reduces microglial activation in MS.MethodsWe measured microglial activation using the 18-kDa translocator protein (TSPO)-binding radioligand [11C]PK11195 and PET imaging in 10 patients with MS before and after 1 year treatment with natalizumab. Microglial activation was evaluated as the distribution volume ratio (DVR) of the specifically bound radioligand in brain white and gray matter regions of interest. MRI and disability measurements were performed for comparison. Evaluation was performed identically with 11 age- and sex-matched patients with MS who had no MS therapy.ResultsNatalizumab treatment reduced microglial activation in the normal-appearing white matter (NAWM; baseline DVR vs DVR after 1 year of treatment 1.25 vs 1.22, p = 0.014, Wilcoxon) and at the rim of chronic lesions (baseline DVR vs DVR after 1 year of treatment 1.24 vs 1.18, p = 0.014). In patients with MS with no treatment, there was an increase in microglial activation at the rim of chronic lesions (1.23 vs 1.27, p = 0.045). No alteration was observed in microglial activation in gray matter areas. In the untreated patient group, higher microglial activation at baseline was associated with more rapid disability progression during an average of 4 years of follow-up.ConclusionsTSPO-PET imaging can be used as a tool to assess longitudinal changes in microglial activation in the NAWM and in the perilesional areas in the MS brain in vivo. Natalizumab treatment reduces the diffuse compartmentalized CNS inflammation related to brain resident innate immune cells.

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[18f]Feppa Pet Imaging For Monitoring Neuroinflammation In Nonhuman Primates

10.21203/rs.3.rs-17421/v1 ◽

2020 ◽

Author(s):

Matthew Zammit ◽

Yunlong Tao ◽

Miles Olsen ◽

Jeanette Metzger ◽

Scott Vermilyea ◽

...

Keyword(s):

Pet Imaging ◽

Microglial Activation ◽

Nonhuman Primates ◽

Rhesus Macaques ◽

Induced Pluripotent Stem Cell ◽

Asymmetry Index ◽

Translocator Protein ◽

Imaging Data ◽

Positron Emission

Abstract Purpose The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [ 18 F]FEPPA has the sensitivity for detecting changes in microglial activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA). Methods In vivo positron emission tomography (PET) imaging with [ 18 F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration. Results Based on visual inspection of the imaging data and assessment of radiotracer uptake, nonhuman primates with allogeneic grafts showed increased [ 18 F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = -0.110 ± 0.025. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral nucleus (p = 0.0004). [ 18 F]FEPPA PET standard uptake values normalized to the contralateral putamen (SUV norm ) showed a positive correlation with CD68 immunoreactivity ratings in the monkeys (Pearson’s r = 0.83; p = 0.0008). Conclusion These findings reveal that [ 18 F]FEPPA PET is an effective marker for detecting increased microglial activation and demonstrate sufficient sensitivity to detect small changes in neuroinflammation in vivo following allogeneic cell engraftment.

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[18F]Florbetapir PET/MR imaging to assess demyelination in multiple sclerosis

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-019-04533-y ◽

2019 ◽

Vol 47 (2) ◽

pp. 366-378 ◽

Cited By ~ 1

Author(s):

Antonio Carotenuto ◽

Beniamino Giordano ◽

George Dervenoulas ◽

Heather Wilson ◽

Mattia Veronese ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Mr Imaging ◽

Pet Imaging ◽

Diffusion Tensor ◽

Volume Ratio ◽

Reference Method ◽

Healthy Controls ◽

Normal Appearing White Matter

Abstract Purpose We evaluated myelin changes throughout the central nervous system in Multiple Sclerosis (MS) patients by using hybrid [18F]florbetapir PET-MR imaging. Methods We included 18 relapsing-remitting MS patients and 12 healthy controls. Each subject performed a hybrid [18F]florbetapir PET-MR and both a clinical and cognitive assessment. [18F]florbetapir binding was measured as distribution volume ratio (DVR), through the Logan graphical reference method and the supervised cluster analysis to extract a reference region, and standard uptake value (SUV) in the 70–90 min interval after injection. The two quantification approaches were compared. We also evaluated changes in the measures derived from diffusion tensor imaging and arterial spin labeling. Results [18F]florbetapir DVRs decreased from normal-appearing white matter to the centre of T2 lesion (P < 0.001), correlated with fractional anisotropy and with mean, axial and radial diffusivity within T2 lesions (coeff. = −0.15, P < 0.001, coeff. = −0.12, P < 0.001 and coeff. = −0.16, P < 0.001, respectively). Cerebral blood flow was reduced in white matter damaged areas compared to white matter in healthy controls (−10.9%, P = 0.005). SUV70–90 and DVR are equally able to discriminate between intact and damaged myelin (area under the curve 0.76 and 0.66, respectively; P = 0.26). Conclusion Our findings demonstrate that [18F]florbetapir PET imaging can measure in-vivo myelin damage in patients with MS. Demyelination in MS is not restricted to lesions detected through conventional MRI but also involves the normal appearing white matter. Although longitudinal studies are needed, [18F]florbetapir PET imaging may have a role in clinical settings in the management of MS patients.

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[18F]VUIIS1009B Features a Superior Imaging Performance to [18F]DPA-714 in TSPO Density Characterization for Neuroinflammatory PET Imaging

10.21203/rs.3.rs-39569/v2 ◽

2020 ◽

Author(s):

Chen Huang ◽

Fan Ding ◽

Yong Hao ◽

Zhoumi Hu ◽

Cheng Wang ◽

...

Keyword(s):

Pet Imaging ◽

Rat Model ◽

Density Measurement ◽

Volume Ratio ◽

Distribution Volume ◽

Translocator Protein ◽

Binding Potential ◽

Great Promise ◽

Parametric Images

Abstract Purpose: Translocator protein (TSPO), an outer mitochondrial membrane protein, is regarded as a key biomarker for neuroinflammation in a variety of neurodegenerative diseases. In this study, we aim to evaluate two highly specific TSPO radiotracers [18F]VUIIS1009A and [18F]VUIIS1009B in a mild cerebral ischemic rat model, and to compare their in vivo performance to the well-established TSPO probe [18F]DPA-714 for neuroinflammation imaging. With multiple graphic analytical methods tested and macro parameters determined, we propose to find a suitable and best quantification method to profile neuroinflammation and measure TSPO density with the three TSPO radiotracers.Methods: Cerebral ischemia rat model was created and imaged using [18F]VUIIS1009A, [18F]VUIIS1009B and [18F]DPA-714. Displacement studies using non-radioactive analogs were performed to evaluate the binding specificities of [18F]VUIIS1009A and [18F]VUIIS1009B individually. Imaging analysis using arterial plasma input functions (AIFs) was employed to generate Logan plots and parametric images of total distribution volume (VT) for each radiotracer. Reference Logan model using contralateral brain as a reference region was introduced to generate parametric images for binding potential (BPND). Results: When compared to [18F]DPA-714, [18F]VUIIS1009B demonstrated higher binding potential (BPND) and distribution volume ratio (DVR). Parameter images of BPND and VT also indicate [18F]VUIIS1009B has a superior imaging profile with higher BPND and DVR when compared with other two radiotracers in TSPO imaging. Correlation analysis between BPND for [18F]VUIIS1009B and [18F]DPA-714 also indicates [18F]VUIIS1009B is more sensitive than [18F]DPA-714 in TSPO density measurement.Conclusions: This study demonstrates the superiority of [18F]VUIIS1009B to [18F]VUIIS1009A and [18F]DPA-714 in the neuroinflammation imaging. It also demonstrates that [18F]VUIIS1009B PET imaging coupled with parameter mapping (VT and BPND) and graphic analysis using Logan analysis and reference Logan analysis holds great promise for neuroinflammation characterization and TSPO density measurement.

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