Teemu Paavilainen

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.

Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis

Post‐partum relapses are a frequent phenomenon in multiple sclerosis (MS). The purpose of this study was to evaluate the timing and extent of new or growing T2‐lesions after delivery in a cohort of Finnish MS patients. In addition to serial magnetic resonance imaging (MRI), the patients were followed up clinically with determination of relapse rate and expanded disability status scale. The annualized relapse rate was decreased during the last trimester of pregnancy [mean 0.14, standard deviation (SD) 0.14] when compared with the time before pregnancy (mean 0.64, SD 0.14; P = 0.04) and to time post‐partum (mean 1.50, SD 0.45; P = 0.0002). New or enlarging lesions were detected in the post‐partum images in 14 of 28 patients. Gadolinium‐enhancing lesions in post‐partum MRI were present in eight of 13 patients. There was a significant increase in the number of T2‐lesions (P = 0.0009), in the total volume of MS‐lesions measured from fluid‐attenuated inversion recovery images (P = 0.0126) and in the number of diffusion weighted imaging hyperintense lesions (P = 0.0098) in the post‐partum images. The clinical results support the earlier findings of decreased disease activity in late pregnancy. The clinical and MRI findings indicate that post‐partum activation is an early and common phenomenon amongst mothers with MS.

Carbon monoxide poisoning-induced nigrostriatal dopaminergic dysfunction detected using positron emission tomography (PET)

A malfunctioning heater caused a severe carbon monoxide (CO) intoxication leading to unconsciousness and predominantly right-sided extrapyramidal syndrome in a 29-year-old man. Follow-up included thorough clinical monitoring, and brain MRI and PET studies. Nine days after the poisoning, brain MRI showed symmetrical necrosis in the globus pallidi, but no abnormality was found in the substantia nigra. In addition, white matter periventricular lesions were seen. In a control scan 14 months later the white matter changes had subsided but small necrotic lesions were still noted bilaterally in the globus pallidi. A 6-[(18)F]fluoro-L-dopa PET examination performed 5 weeks after the intoxication revealed impaired presynaptic dopaminergic function in the left putamen whereas in the right putamen the dopaminergic activity was within normal limits. [(11)C] raclopride PET imaging 4 months after the poisoning showed no abnormality in postsynaptic D2 binding in the striatum. Clinically, the parkinsonian symptoms resolved 1.5 years after the poisoning. The final outcome of the recovery was excellent, and the patient returned to work. This is the first case reported where unilateral presynaptic, dopaminergic hypofunction in putamen could be confirmed with fluoro-l-dopa PET imaging on a patient with extrapyramidal syndrome caused by CO poisoning. Our results emphasize that CO intoxication can lead to striatal dopaminergic hypofunction, and that PET is a sensitive tool in evaluating extrapyramidal system after sudden neurotoxic insult.

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.

Diffusion tensor imaging and brain volumetry in Fabry disease patients

IntroductionFabry disease is a rare lysosomal storage disorder leading to cellular accumulation of globotriaosylceramide, especially in blood vessels. It is associated with severe early onset cerebrovascular disease and kidney and heart failure. The purpose of this study was to reveal possible disturbances in white matter integrity in Fabry disease patients using voxelwise diffusion-tensor imaging (DTI) analysis.MethodsTwelve Fabry disease patients, along with 13 healthy controls, underwent DTI and structural MRI. Voxel-based analysis of the DTI data was performed to assess possible differences in DTI parameters between Fabry disease patients and healthy controls. A selective region of interest analysis was performed for healthy volunteers and Fabry disease patients having a mild burden of T2-hyperintense lesions. We also measured normalised brain tissue volumes and performed a voxel-based volume analysis for grey matter.ResultsVoxel-based analysis of DTI data showed areas of significantly reduced fractional anisotropy and increased mean diffusivity in patients with Fabry disease. Eight patients had a mild burden of white matter lesions on their T2 scans. Region of interest analysis on areas showing reduced fractional anisotropy in voxelwise analysis also revealed reduced fractional anisotropy values in this patient group compared to eight healthy volunteers. The brain volume analyses did not reveal significant differences between the Fabry disease patients and the controls.ConclusionThese findings suggest a microstructural damage in brain white matter of Fabry disease patients, which can be revealed before excessive white matter lesions load is visible on conventional MR scans.

Fractional anisotropy and mean diffusivity parameters of the brain white matter tracts in preterm infants: reproducibility of region-of-interest measurements

BackgroundDiffusion tensor parameters can be analysed by fitting regions of interest (ROIs) to selected brain structures. The clinical usefulness of these measurements is influenced by their reproducibility and validity.ObjectiveTo investigate the reproducibility of fractional anisotropy (FA) and mean diffusivity (MD) measurements.Material and methodsSeventy-six infants were imaged once at term-equivalent age. We measured several brain regions. Reproducibility was assessed using intraclass correlation coefficient and Bland-Altman method.ResultsIntra-observer reproducibility was excellent for FA in the calcarine cortex (right) and frontal white matter (left), and for MD in the corpus callosum (anterior), internal capsule, corona radiata, putamen, frontal white matter, optic radiation (left), thalamus (right) and calcarine cortex (right). Inter-observer reproducibility was excellent for FA in the corpus callosum (posterior) and for MD in the internal capsule and corona radiata (right). Inter-observer reproducibility was poor for FA in frontal and posterior white matter (right) and for MD in the inferior colliculus (right). Reproducibility was fair to good in other areas. The Bland-Altman plots showed no considerable bias, and variance was independent of the mean value.ConclusionReproducibility of ROI measurement was fair to good for both FA and MD.

Methanol intoxication-induced nigrostriatal dysfunction detected using 6-[18F]fluoro-l-dopa PET

Ingestion of windshield washer liquid resulted with an acute severe methanol intoxication in a 49-year old man. He developed optic atrophy with blindness, and an extrapyramidal syndrome. Putaminal injury and hyperintensity in the subcortical white matter was seen in a brain MRI. PET scanning with 6-[18F]fluoro-L-dopa confirmed symmetrical impaired presynaptic dopaminergic activity in the striatum, indicative of functional impairment of dopaminergic nigrostriatal neurons. The striatal uptake was more markedly impaired in the putamina (40% of controls) than in the caudate nuclei (60% of controls). To our knowledge, this is the first report of an 18F-dopa PET scanning result in a case of an acute methanol poisoning.

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.

Apparent Diffusion Coefficient Histograms in the Follow-up of Relapsing-Remitting Multiple Sclerosis.

Diffusion-weighted (DW) magnetic resonance (MR) imaging in addition to conventional magnetic resonance MR images provide valuable information in multiple sclerosis (MS). Increased diffusivity measured with diffusion-weighted imaging (DWI) has been demonstrated in normal appearing brain tissue in MS. So far, longitudinal changes taking place in whole-brain histograms in patients with active relapsing-remitting MS have not been evaluated. The aim of this study was to evaluate how apparent diffusion coefficient (ADC) histograms are altered during the follow-up of active relapsing-remitting MS patients. Nine patients were studied twice by MRI with a three-month interval. All patients had active newly diagnosed MS with two to three relapses during the year preceding the first MRI, and interferon-beta treatment was initiated after obtaining the first image. ADC histograms were produced after removing extracranial tissues and cerebrospinal fluid from the images. Additionally, brain volume index (BVI) and lesion volume on FLAIR images were measured. Five patients had signs of disease activity in the follow-up MRI. In the four patients without signs of disease activity the change in ADC histogram parameters was less than 2%. In patients with disease activity both increase (one case) and decrease (four cases) in histogram parameters were detected. Changes in BVI or lesion volume did not significantly correlate with histogram changes. The number of new T2-lesions showed a positive correlation with mean (r=0.79, P=0.014) and upper quartile (r=0.77, P=0.021) value change. Alterations in disease activity lead to histogram changes; both shifts to lower values and shifts to higher values are possible. The histogram changes are mostly related to subtle inflammatory changes in normal appearing brain tissue during inflammatory activity and their resolution during less active inflammatory conditions.