Jouni Tuisku

In Vivo Detection of Diffuse Inflammation in Secondary Progressive Multiple Sclerosis Using PET Imaging and the Radioligand 11C-PK11195

Patients with secondary progressive multiple sclerosis (SPMS) are lacking efficient medication to slow down the progression of their disease. PET imaging holds promise as a method to study, at the molecular level and in vivo, the central nervous system pathology of SPMS. PET might thus help to elucidate potential therapeutic targets and be useful as an imaging biomarker in future treatment trials of progressive multiple sclerosis. The objective of this study was to evaluate whether translocator protein (TSPO) imaging could be used to visualize the diffuse inflammation located in the periplaque area and in the normal-appearing white matter (NAWM) in the brains of patients with SPMS. Methods: This was an imaging study using MR imaging and PET with 11C-PK11195 binding to TSPO, which is expressed in activated, but not in resting, microglia. Ten SPMS patients with a mean expanded disability status scale score of 6.3 (SD, 1.5) and eight age-matched healthy controls were studied. The imaging was performed using High-Resolution Research Tomograph PET and 1.5-T MR imaging scanners. Microglial activation was evaluated as the distribution volume ratio (DVR) of 11C-PK11195 from dynamic PET images. DVR estimations were performed with special interest in NAWM and gray matter using region-of-interest and parametric image–based approaches. Results: The DVR of 11C-PK11195 was significantly increased in the periventricular and total NAWM (P = 0.016 and P < 0.001, respectively) and in the thalamic ROIs (P = 0.027) of SPMS patients, compared with the control group. Similarly, parametric image analysis showed widespread increases of 11C-PK11195 in the white matter of SPMS patients, compared with healthy controls. Increased perilesional TSPO uptake was present in 57% of the chronic T1 lesions in MR imaging. Conclusion: The finding of increased 11C-PK11195 binding in the NAWM of SPMS patients is in line with the neuropathologic demonstration that activated microglial cells are the source of diffuse NAWM inflammation. Evaluating microglial activation with TSPO-binding PET ligands provides a unique tool to assess diffuse brain inflammation and perilesional activity in progressive multiple sclerosis in vivo.

Adenosine A2A Receptors in Secondary Progressive Multiple Sclerosis: A [11C]TMSX Brain PET Study:

In this study, positron emission tomography (PET) imaging with a radioligand to adenosine A2A receptors (A2AR)—a potent regulator of inflammation—was used to gain insight into the molecular alterations in normal-appearing white matter (NAWM) and gray matter (GM) in secondary progressive multiple sclerosis (SPMS). Normal-appearing white matter and GM, despite seeming normal in conventional mangnetic resonance imaging (MRI), are important loci of widespread inflammation, neuronal damage, and source of progressive disability in multiple sclerosis (MS). Dynamic PET imaging using A2AR-specific [ 11 C]TMSX and brain MRI with diffusion tensor imaging were performed to eight SPMS patients and seven healthy controls. Distribution volumes (VT) of [ 11 C]TMSX were analyzed from 13 regions of interest using Logan plot with arterial plasma input. The SPMS patients had significantly increased [ 11 C]TMSX-VT in NAWM compared with controls (mean (s.d.): 0.55 (± 0.08) vs. 0.45 (± 0.05);P = 0.036). Both the increased VT and the decreased fractional anisotropy (FA) in NAWM were associated with higher expanded disability status scale (EDSS) scores (P = 0.030 and P = 0.012, respectively), whereas the T2-lesion load of SPMS patients did not correlate with EDSS. This study shows, that A2ARs are increased in the brain of SPMS patients, and that [ 11 C]TMSX-PET provides a novel approach to learn about central nervous system pathology in SPMS in vivo.

Evaluation of the effect of fingolimod treatment on microglial activation using serial PET imaging in multiple sclerosis

Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)–binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of 11C‐(R)-PK11195. Results: The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). 11C‐(R)-PK11195 binding was reduced (−12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.

Microglial activation, white matter tract damage, and disability in MS

Objective To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS. Methods Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison. Results [11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls. Conclusions PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.

Performance of an image-based motion compensation algorithm for the hrrt: A striatum-phantom study with true motion

High Resolution Research Tomograph (HRRT, Siemens) is a dedicated human brain PET scanner with nearly isotropic and shift invariant reconstructed resolution of 2.5 mm (FWHM) as measured using a point source and reconstruction settings of NEMA standard [1]. Spatial resolution can be however significantly degraded if the imaged object is moving during PET scanning resembling impact of partial volume effect (PVE). Head motion is particularly detrimental in brain studies investigating e.g. tracer receptor binding in the small brain nuclei, and their displacement thereof. In fact, decreased tracer uptake as depicted by time-activity curve (TAC) data may often be due to head motion rather than inhibition of tracer binding (c.f. [2]).

Tissue Probability-Based Attenuation Correction for Brain PET/MR by Using SPM8

Bone attenuation remains a methodological challenge in hybrid PET/MR, as bone is hard to visualize via magnetic resonance imaging (MRI). Therefore, novel methods for taking into account bone attenuation in MR-based attenuation correction (MRAC) are needed. In this study, we propose a tissue-probability based attenuation correction (TPB-AC), which employs the commonly available neurological toolbox SPM8, to derive a subject-specific μ-map by segmentation of T1-weighted MR images. The procedures to derive a μ-map representing soft tissue, air and bone from the New Segment function in SPM8 and MATLAB are described. Visual and quantitative comparisons against CT-based attenuation correction (CTAC) data were performed using two μ-values ( 0.135 cm-1 and 0.145 cm-1) for bone. Results show improvement of visual quality and quantitative accuracy of positron emission tomography (PET) images when TPB-AC μ-map is used in PET/MR image reconstruction. Underestimation in PET images was decreased by an average of 5 ±2 percent in the whole brain across all patients. In addition, the method performed well when compared to CTAC, with maximum differences (mean ± standard deviation) of - 3 ±2 percent and 2 ±4 percent in two regions out of 28. Finally, the method is simple and computationally efficient, offering a promising platform for further development. Therefore, a subject-specific MR-based μ-map can be derived only from the tissue probability maps from the New Segment function of SPM8.

Microglial activation correlates with disease progression in multiple sclerosis

OBJECTIVE: The aim of this cross-sectional study was to investigate how activation of microglia correlates to certain milestones related to MS progression. BACKGROUND: Activation of microglia is considered a crucial step in CNS response to injury. Measuring microglial activation in vivo is possible using PET imaging and radioligands binding to 18 kDa translocator protein (TSPO). DESIGN/METHODS: MS patients with secondary progressive (SPMS, n=10) or relapsing remitting (RRMS, n=10) disease, and healthy controls (n=8) were imaged using PET and the TSPO-binding radioligand 11C-PK11195. Microglial activation was evaluated as distribution volume ratio (DVR) of 11C-PK11195-binding from dynamic PET images. Diffusion tensor imaging was performed for assessment of structural integrity of the normal appearing white matter (NAWM) tracts. RESULTS: 11C-PK11195 binding was significantly increased in the perilesional white matter and in the NAWM of SPMS compared to RRMS patients (p=0.011 and p<0.001, respectively). A DVR cut-off value of 1.02 in 11C-PK11195 binding in the NAWM separated the RRMS and SPMS groups from each other. The increased radioligand binding in perilesional WM and NAWM correlated to increasing clinical disability measured using EDSS (p=0.030 and p<0.001 respectively). Lower fractional anisotropy in the NAWM also correlated to higher EDSS (p=0.002). CONCLUSIONS: TSPO PET imaging can be used as an imaging biomarker of diffuse neuroinflammation related to disease progression in MS. Disclosure: Dr. Airas has nothing to disclose. Dr. Rissanen has nothing to disclose. Dr. Tuisku has nothing to disclose. Dr. Rinne has received research support from Orion Pharma, Pfizer, Bristol-Myers-Squibb, GE, Noscira, Roche and AC-Immune.

Tissue probability-based AC for neurological PET/MR using SPM8

The quantitative accuracy of brain PET/MR has been reported to be reduced compared to PET/CT due to difficulties related to bone in MR-based attenuation correction (MRAC), especially in regions near the skull. To reduce these effects, we designed an offline, tissue probability-based (TPB-AC) using SPM8, which includes soft tissue, air and bone. Thus, both the increased attenuation due to skull and the reduced attenuation due to sinuses are taken into account. The method was developed to use the data collected with the standard anatomical MRAC consisting of 3D T1 FFE, with isotropic voxel size of 2 mm. Thus, collection of additional sequences or modifications to the standard attenuation correction sequence are not required. Data from F18-FDG brain studies performed both with PET/CT and PET/MR was used in AC validation. Seven patients were reconstructed with the standard attenuation map, TPB-AC and CTAC in PET/MR. Regional analysis between attenuation corrected PET images was conducted using CTAC as reference. Using TPB-AC, the relative difference in seven subjects when compared to CTAC in all regions was -3 %, -2 %, -5 %, 4 %, -3 %, 1 %, 0 %. In clinical AC the difference was -9 %, -8 %, -9 %, -3 %, -10 %, -5 %, -6 %. Region-wise, the benefit from TPB-AC was most pronounced in precentral, superior frontal and middle frontal gyrus where underestimation from clinical AC of: -11 %, -12 % and -12 % was reduced to: -1%, -2 % and -1 % when using TPB-AC. Tissue probability-based AC was deemed a promising interim method for PET/MR AC until standardized, commercialized solutions become widely available. To test the robustness of the method, patients with dental implants or deformed anatomy would have to be included in the study group.

Quantitative evaluation of two scatter correction techniques for 18F-FDG brain PET/MR imaging in regard to MR-based attenuation correction

In PET, corrections for photon scatter and attenuation are essential for visual and quantitative consistency. MR attenuation correction (MRAC) is generally conducted by image segmentation and assignment of discrete attenuation coefficients, which offer limited accuracy compared with CT attenuation correction. Potential inaccuracies in MRAC may affect scatter correction, because the attenuation image (μ-map) is used in single scatter simulation (SSS) to calculate the scatter estimate. We assessed the impact of MRAC to scatter correction using 2 scatter-correction techniques and 3 μ-maps for MRAC. Methods: The tail-fitted SSS (TF-SSS) and a Monte Carlo–based single scatter simulation (MC-SSS) algorithm implementations on the Philips Ingenuity TF PET/MR were used with 1 CT-based and 2 MR-based μ-maps. Data from 7 subjects were used in the clinical evaluation, and a phantom study using an anatomic brain phantom was conducted. Scatter-correction sinograms were evaluated for each scatter correction method and μ-map. Absolute image quantification was investigated with the phantom data. Quantitative assessment of PET images was performed by volume-of-interest and ratio image analysis. Results: MRAC did not result in large differences in scatter algorithm performance, especially with TF-SSS. Scatter sinograms and scatter fractions did not reveal large differences regardless of the μ-map used. TF-SSS showed slightly higher absolute quantification. The differences in volume-of-interest analysis between TF-SSS and MC-SSS were 3% at maximum in the phantom and 4% in the patient study. Both algorithms showed excellent correlation with each other with no visual differences between PET images. MC-SSS showed a slight dependency on the μ-map used, with a difference of 2% on average and 4% at maximum when a μ-map without bone was used. Conclusion: The effect of different MR-based μ-maps on the performance of scatter correction was minimal in non–time-of-flight 18F-FDG PET/MR brain imaging. The SSS algorithm was not affected significantly by MRAC. The performance of the MC-SSS algorithm is comparable but not superior to TF-SSS, warranting further investigations of algorithm optimization and performance with different radiotracers and time-of-flight imaging.

Brain positron emission tomography scanning can be used to image pathological determinants of progressive multiple sclerosis

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS and demyelination and axonal damage are responsible for neurological deficits in MS. However, the pathological changes that underlie these morphologies are not fully understood. To address this issue, myelin basic protein-deficient shiverer mice and mice with experimental autoimmune encephalomyelitis (EAE) were examined how the morphological differences of myelin and the axon were induced by dysmyelination and demyelination. Here we used osmium-maceration scanning electron microscopic (SEM) analysis. Osmium-maceration SEM displayed clear variations in the ultrastructural abnormalities of myelin structure and axonal organelles in the white matter of the EAE spinal cord. For example, myelin detachment and excess myelin formation were observed as typical abnormalities of myelin during demyelination in EAE. Importantly, compact myelin was well preserved even though in these situations. SEM images also showed the morphological changes of axonal intracellular organelles during demyelination. Enriched mitochondria and well-developed sER-like structures were observed in the axons of the EAE spinal cord. These observations were also found in the axon of shiverer mice. Taken together, these results indicate that there is a close relationship between myelin and axon morphology during demyelination.