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.

Download Full-text

T1 relaxation maps allow differentiation between pathologic tissue subsets in relapsing-remitting and secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1073oa ◽

2004 ◽

Vol 10 (5) ◽

pp. 556-561 ◽

Cited By ~ 15

Author(s):

A Castriota-Scanderbeg ◽

F Fasano ◽

M Filippi ◽

C Caltagirone

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Relaxation Times ◽

Brain Regions ◽

Progressive Multiple Sclerosis ◽

Clinical Group ◽

Secondary Progressive ◽

Normal Appearing White Matter ◽

Relapsing Remitting ◽

Normal White Matter

In an attempt to clarify whether T1 relaxation time mapping may assist in characterizing the pathological brain tissue substrate of multiple sclerosis (MS), we compared the T1 relaxation times of lesions, areas of normal-appearing white matter (NAWM) located proximal to lesions, and areas of NAWM located distant from lesions in 12 patients with the relapsing-remitting and 12 with the secondary progressive (SP) subtype of disease. Nine healthy volunteers served as controls. Calculated mean T1 values were averaged across all patients within each clinical group, and comparisons were made by means of the Mann-Whitney U-test. Significant differences were found between all investigated brain regions within each clinical subgroup. Significant differences were also detected for each investigated brain region among clinical subgroups. While T1 values of NAWM were significantly higher in patients with SP disease than in normal white matter (NWM) of controls, no differences were detected when corresponding brain areas of patients with RR MS were compared with NWM of controls. T1 maps identify areas of the brain that are damaged to a different extent in patients with MS, and may be of help in monitoring disease progression.

Download Full-text

Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458509103176 ◽

2009 ◽

Vol 15 (6) ◽

pp. 687-694 ◽

Cited By ~ 8

Author(s):

J Furby ◽

T Hayton ◽

D Altmann ◽

R Brenner ◽

J Chataway ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Grey Matter ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Lesion Volume ◽

Secondary Degeneration ◽

Secondary Progressive ◽

Demyelinating Lesions ◽

The Relationship

Background Although MRI measures of grey matter abnormality correlate with clinical disability in multiple sclerosis, it is uncertain whether grey matter abnormality measured on MRI is entirely due to a primary grey matter process or whether it is partly related to disease in the white matter. Methods To explore potential mechanisms of grey matter damage we assessed the relationship of white matter T2 lesion volume, T1 lesion volume, and mean lesion magnetisation transfer ratio (MTR), with MRI measures of tissue atrophy and MTR in the grey matter in 117 subjects with secondary progressive multiple sclerosis. Results Grey matter fraction and mean grey matter MTR were strongly associated with lesion volumes and lesion MTR mean ( r = ±0.63–0.72). In contrast, only weak to moderate correlations existed between white matter and lesion measures. In a stepwise regression model, T1 lesion volume was the only independent lesion correlate of grey matter fraction and accounted for 52% of the variance. Lesion MTR mean and T2 lesion volume were independent correlates of mean grey matter MTR, accounting for 57% of the variance. Conclusions Axonal transection within lesions with secondary degeneration into the grey matter may explain the relationship between T1 lesions and grey matter fraction. A parallel accumulation of demyelinating lesions in white and grey matter may contribute to the association of T2 lesion volume and lesion MTR with grey matter MTR.

Download Full-text

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

Journal of Nuclear Medicine ◽

10.2967/jnumed.113.131698 ◽

2014 ◽

Vol 55 (6) ◽

pp. 939-944 ◽

Cited By ~ 82

Author(s):

E. Rissanen ◽

J. Tuisku ◽

J. Rokka ◽

T. Paavilainen ◽

R. Parkkola ◽

...

Keyword(s):

Multiple Sclerosis ◽

Pet Imaging ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Diffuse Inflammation ◽

In Vivo Detection

Download Full-text

7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis

Brain ◽

10.1093/brain/awaa249 ◽

2020 ◽

Vol 143 (10) ◽

pp. 2973-2987 ◽

Cited By ~ 1

Author(s):

Russell Ouellette ◽

Constantina A Treaba ◽

Tobias Granberg ◽

Elena Herranz ◽

Valeria Barletta ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

White Matter ◽

Cervical Spinal Cord ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Spinal Cord Lesions ◽

Secondary Progressive ◽

Relapsing Remitting

Abstract We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

Download Full-text

White matter tract abnormalities are associated with cognitive dysfunction in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515622694 ◽

2016 ◽

Vol 22 (11) ◽

pp. 1429-1437 ◽

Cited By ~ 19

Author(s):

Kim A Meijer ◽

Nils Muhlert ◽

Mara Cercignani ◽

Varun Sethi ◽

Maria A Ron ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Cognitive Domains ◽

Secondary Progressive ◽

Relapsing Remitting ◽

Magnetic Resonance Imaging Mri ◽

Relapsing Remitting Multiple Sclerosis ◽

Tract Damage

Background: While our knowledge of white matter (WM) pathology underlying cognitive impairment in relapsing remitting multiple sclerosis (MS) is increasing, equivalent understanding in those with secondary progressive (SP) MS lags behind. Objective: The aim of this study is to examine whether the extent and severity of WM tract damage differ between cognitively impaired (CI) and cognitively preserved (CP) secondary progressive multiple sclerosis (SPMS) patients. Methods: Conventional magnetic resonance imaging (MRI) and diffusion MRI were acquired from 30 SPMS patients and 32 healthy controls (HC). Cognitive domains commonly affected in MS patients were assessed. Linear regression was used to predict cognition. Diffusion measures were compared between groups using tract-based spatial statistics (TBSS). Results: A total of 12 patients were classified as CI, and processing speed was the most commonly affected domain. The final regression model including demographic variables and radial diffusivity explained the greatest variance of cognitive performance ( R2 = 0.48, p = 0.002). SPMS patients showed widespread loss of WM integrity throughout the WM skeleton when compared with HC. When compared with CP patients, CI patients showed more extensive and severe damage of several WM tracts, including the fornix, superior longitudinal fasciculus and forceps major. Conclusion: Loss of WM integrity assessed using TBSS helps to explain cognitive decline in SPMS patients.

Download Full-text

Conversion of diffusely abnormal white matter to focal lesions is linked to progression in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520912172 ◽

2020 ◽

pp. 135245852091217

Author(s):

Mahsa Dadar ◽

Sridar Narayanan ◽

Douglas L Arnold ◽

D Louis Collins ◽

Josefina Maranzano

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis ◽

Magnetic Resonance Images ◽

Secondary Progressive Multiple Sclerosis ◽

Clinical Progression ◽

Focal Lesions ◽

Secondary Progressive ◽

Over Time

Background: Diffusely abnormal white matter (DAWM) regions are observed in magnetic resonance images of secondary progressive multiple sclerosis (SPMS) patients. However, their role in clinical progression is still not established. Objectives: To characterize the longitudinal volumetric and intensity evolution of DAWM and focal white matter lesions (FWML) and assess their associations with clinical outcomes and progression in SPMS. Methods: Data include 589 SPMS participants followed up for 3 years (3951 time points). FWML and DAWM were automatically segmented. Screening DAWM volumes that transformed into FWML at the last visit (DAWM-to-FWML) and normalized T1-weighted intensities (indicating severity of damage) in those voxels were calculated. Results: FWML volume increased and DAWM volume decreased with an increase in disease duration ( p < 0.001). The Expanded Disability Status Scale (EDSS) was positively associated with FWML volumes ( p = 0.002), but not with DAWM. DAWM-to-FWML volume was higher in patients who progressed (2.75 cm3 vs. 1.70 cm3; p < 0.0001). Normalized T1-weighted intensity of DAWM-to-FWML was negatively associated with progression ( p < 0.00001). Conclusion: DAWM transformed into FWML over time, and this transformation was associated with clinical progression. DAWM-to-FWML voxels had greater normalized T1-weighted intensity decrease over time, in keeping with relatively greater tissue damage. Evaluation of DAWM in progressive multiple sclerosis provides a useful measure for therapies aiming to protect this at-risk tissue with the potential to slow progression.

Download Full-text