Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study
Versijpt J, Debruyne JC, Van Laere KJ, De Vos F, Keppens J, et al. ;
Commented by , 21 Apr 2005
Background
It has been hypothesized that activation of microglia is one of the central pathophysiological events in MS. Various stimuli such as proinflammatory cytotoxic cytokines, matrix metalloproteinases, free radicals and nitric oxide cause microglia activation.
This may lead to release of myelinotoxic factors that directly injure the oligodendrocyte-myelin unit. Activated microglia express the peripheral benzodiazepine receptor and visualization of this receptor can be performed using the radiolabelled high affinity ligand PK11195.
In the current study the authors investigate the relationship between activated microglia and cerebral atrophy, which is considered to be the pathological end point of MS.
Aim
To compare measurements of brain atrophy in MS with normal controls and to correlate this with clinical measurements. To correlate 11C-PK11195 uptake with brain atrophy.
Methods
The authors examined 8 controls and 22 MS patients (13 with relapsing-remitting and 7 with secondary progressive. Six patients had clinical relapse and 10 had Gd-enhancing lesions on MRI at the time of examination. Average disease duration was 9.3 years and average disability (EDSS) was 4.0.
A slow bolus of approximately 370 MBq 11C-PK11195 was administered i.v. and semiquantitative measurement of cerebral tracer uptake was performed using positron emission tomography (PET).
A 1.5 tesla MRI with Gd-enhancement was performed for evaluation of disease burden and activity, selection of regions of interest (ROI’s) as well as measurements of brain parenchymal fraction (relative atrophy measurement).
For statistical evaluation the authors used t-test or Mann-Whitney U test for differences between groups and Spearman or Pearson test was used for correlation analysis.
Results
There was a statistically significant correlation between 11C-PK11195 in NAWM and cerebral atrophy (r=-0.2; P=0.03).
The 11C-PK11195 uptake for T2 lesions decreased and correlated with increasing brain atrophy (r=-0.3; P=0.03).
Atrophy was more pronounced in MS patients compared with normal subjects.
The presence of relapse and enhancing lesions did not predict the amount of brain atrophy.
Dr Blinkenberg's comments
The study shows a weak correlation between 11C-PK11195 uptake and cerebral atrophy. It is the first study showing a relationship between subtle inflammatory changes in normal appearing white matter (NAWM) and axonal/neuronal loss in MS in vivo.
In this way the study corroborate the notion that diffuse pathophysiological processes in NAWM may cause early and ongoing cerebral atrophy, which also has been shown using MR spectroscopy and magnetization transfer.
There are some methodological drawbacks of the study, the most important being the semiquantitative approach, where PET tracer measurements are normalized to grey matter, on the assumption that grey matter is relatively unaffected. This will inevitably underestimate tracer uptake estimates in subjects with cortical disease involvement, which is known to be more pronounced in MS than previously assumed.
Concerning small regions of interest there is also a risk of underestimating tracer uptake caused by partial volume effect, which was not corrected.
Still the PET 11C-PK11195 technique is interesting and with some methodological refinement (quantification) important questions regarding pathophysiology may be explained, e.g. difference in tracer distribution between different courses of disease, prognosis due to difference in tracer uptake, effect of treatment with various medications etc.