Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis

Abstract

To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18 F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n=37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n=19) underwent magnetic resonance magnetic and 18 F-DPA-714 PET. A threshold of significant activation of 18 F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.99.7%; WM in controls=14.07.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.113.5%, 45.017.9%, and 51.922.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPAactive and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, p=0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, p=0.009) and in T1-spin-echo lesions (OR=1.06, p=0.036), were significantly associated by Imperial College London Library on February 11, 2020. For personal use only. jnm.snmjournals.org Downloaded from 2 with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. 18 F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory.

Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

“…The PET protocol consisted of an IV bolus injection of 198.4 ± 22.9 MBq of [ 18 F]-DPA714 at the beginning of a 90-minute dynamic acquisition, as previously detailed. 24 , 25 After reconstruction, the resulting dynamic PET images consisted of 27 time interval (time frames) images: six 1-minute frames for the initial 6 minutes (6 × 1), followed by 7 × 2-minute frames and 14 × 5-minute frames, with a spatial resolution of ≈2.5-mm full width at half-maximum.…”

“…The 20% relative threshold had been calculated by means of a voxel-wise nonparametric permutation-based t test between the DVR maps of patients and HC, as previously described. 25 This step resulted in the generation of individual maps of innate immune cells activation, consisting of binary masks of DPA+ voxels ( figure 2B ).…”

“…were identified as those voxels whose DVR value exceeded of more than 20% the mean DVR value of the healthy controls in the same MNI position. The 20% relative threshold had been previously calculated by means of a voxel-wise non-parametric permutationbased t-test between the DVR maps of patients and healthy controls, as previously described 25 . This step resulted in the generation of individual maps of innate immune cells activation, consisting of binary masks of DPA+ voxels ( Fig 2B).…”

Have (R)-[11C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies

“…Diffuse neuroinflammation in normal appearing white-matter and in normal appearing grey matter, was more pronounced in progressive MS than in relapsing-remitting phenotypes [94]. Several studies pointed out the predictive value of TSPO PET ((R)-[ 11 C] PK11195 [110,111], [ 11 C]PBR28 [112], [ 18 F]DPA-714 [113]). Overall, in spite of the complexity brought by the different MS subtypes, results from (R)-[ 11 C]PK11195 and challenger studies were in accordance.…”

DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

“…Disability closely mirrors neuro-axonal deterioration, irrespective of the type of lesions and disease course 2 . While inflammation is unambiguously observed at all stages of the disease, compartmentalized chronic inflammation orchestrated by resident CNS cells dominate later stages of the disease, independently of immune infiltrates or pre-existing demyelination and accounts for the clinical trajectory [3][4][5] . Ultimately, persistent inflammation and recurrent damage to the myelin insulating axons will eventually exhaust the repair capacity of the nervous tissue 6,7 , a weakened functional recovery presaging transition to the progressive stage of the disease.…”