Imaging activated microglia in relapsing remitting multiple sclerosis: a first in human P2X7r PET study

The pathophysiology of MS is currently unclear. Microglia activation can be
used as an indirect marker to assess neuroinflammation in MS. For the past
twenty years this has been studied in MS patients with the use of TSPO PET-
tracers. However, TSPO as microglial imaging target has several limitations,
e.g. intracellular localization, various polymerization states, genetic binding
differences. Therefore, new microglial targets, including the purinergic
receptor family, have been investigated as alternative membrane-based receptors
to serve for in vivo assessment of microglial activation.

To assess activated microglia in vivo in clinically and/or radiologically
active RRMS patients compared to healthy controls using the PET-tracer
[11C]SMW139, to assess retest variability in regional [11C]SMW139 brain uptake,
and to evaluate which tracer kinetic method is the most suitable for
quantification of [11C]SMW139 binding.11C]SMW139 binding.

We will include 10 RRMSpatients and 10 healthy controls. For both the MS
patients and healthy controls this study will consist of three parts:
1. First study visit at the Neurology outpatient clinic for a neurological and
physical examination, questionnaires and venous blood sampling
2. MRI scan, for the patient group with administration of the contrast agent
gadolinium.
3. Two [11C]SMW139 PET-CT scans with arterial blood sampling on the same day
(test-retest)

Risks associated with participation in this study are related tot 1) radiation
exposure, 2) idiosyncratic reaction to the tracer, 3) placement of in
intra-venous and intra-arterial catheter, 4) discomfort during the scanning, 5)
blood sampling, 6) coincidental finding.
1) The two [11C]SMW139 PET-CT scans will result in a total radiation burden of
6 mSv. This falls in de International Commission on Radiological Protection
(ICRP) risk category IIb. Radiation exposure in this category is justified if
it is directly aimed at the cure or prevention of disease, as is the case for
this protocol.
2) Based on the extensive experience with PET-tracers in our center,
idiosyncratic reaction to the venously administered tracer [11C]SMW139 is not
rendered likely. During each injection of the tracer a physician will be
present.
3) Intravenous and intra-arterial cannulation is associated with a very small
risk of infection and bleeding. This will be prevented by the use of proper
techniques by experiences personel.
4) It may be uncomfortable to lie motionless in the MRI and PET scanners and it
may cause some subjects to fell anxious. Subjects will be made acquinted with
the surroundings beforehand. Moreover, our staff will be available to provide
support, reduce anxiety, optimise the comfort of subjects and if requested
remove subjects from the scanner.
5) Adverse effects of blood sampling will be minimised by exclusion of subjects
with low haemogolibin levels (in males Hb < 8.0 mmol/litre, in females Hb < 7.0
mmol/litre). No more than 500 ml blood will be withdrawn during the total PET
procedure and screening.
6) With the blood tests and MRI-scan a coincidental finding may occur. If such
a new finding has consequences for the subject, the subject and his/her general
practitioner will be informed. If a patient or healthy control does not want to
be informed on such a coincidental finding, this subject can not partake in
this trial.