Grey matter microglial imaging with [18F]DPA-714 in progressive MS patients

Multiple sclerosis (MS) is the most common nontraumatic cause of neurologic
disability in young adults. It is an auto-immune disorder characterized by
inflammatory demyelination and axonal transection in multiple sites throughout
the central nervous system. Approximately 80% of patients are initially
diagnosed with relapsing-remitting MS (RRMS), in which patients experience
relapses of neurological symptoms, followed by a complete or partial remission.
With disease progression around 70% of RRMS patients enter a secondary
progressive phase, characterized by a steady progression of neurological
symptoms. This phase is termed secondary progressive MS (SPMS). In the
remaining 20% of patients the disease has a progressive course from disease
onset called primary progressive MS (PPMS).

MS has been traditionally regarded as a white matter disorder; however focal
demyelination in the white matter as shown on MRI cannot fully explain the
neurological and cognitive deficits in MS patients. Histological studies have
shown the involvement of grey matter regions in the demyelinating process in
predominantly PPMS and SPMS. The importance of this was illustrated by the
fact that the extent and severity of cortical/subcortical damage significantly
influence the cognitive functions in MS patients. Histological studies have
shown that grey matter lesions (GML) formation differs from white matter lesion
(WML) formation by a relative absence of infiltrating leukocytes. In line with
this, there is limited blood-brain barrier (BBB) damage in progressive MS. A
recent post-mortem study showed an abundance of microglial reactivity in these
cortical lesions. Combined with the known lack of clinical response of
immune-modulating treatment as used in RRMS in patients with progressive
disease1, these data indicate that the pathogenesis of neurodegeneration may be
different between RRMS and progressive MS phases.

The main objective of this study is to depict microglial activation behind a
closed BBB in vivo and possibly establish an imaging marker of fast clinical
progression, we will aim at visualizing microglial activity in vivo in cortical
and hippocampal grey matter of progressive MS patients, and determine its
relation to cognition and disability.

To quantify activated microglia in vivo we will use the tracer [18F]DPA-714.
This is a second generation TSPO radioligan of which previous studies have
shown a high affinity and specificity for activated microglia. Besides, the
binding to 18F makes this tracer als favourable over other 11C bound TSPO
radioligand as 18F tracers have a significantly longer half life (109.8 minutes
compared to 20.4 minuten). This will increased its clinical use.
For this pilot study we will include 13 PPMS or SPMS patients and 10 healthy
controls.

For both the MS patients and healthy contols this study will consist of three
parts:
1. A screenings session with neurological and physical test, questionaires and
venous blood sampling.
2. MRI scan qith administration of hte contrast agent gadolinium.
3. PET-CT scan with the use of [18F]DPA-714 and with arterial blood sampling.

Intravenous injection of the PET tracer [18F]DPA-714.

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) Administration of 250 MBq of [18F]DPA-714 will result in a radiation dose of
approximately 5.25 mSv. The low-dose CT-scan of the brain gives a radiation
dose of 0.5 mSv, resulting in a total radiation exposure of 5.75 mSv per
subject. 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. This is the case as
the role activated microlgia probably play in neuroinflammation and
neurodegeneration associated with MS could lead to the development of specific
treatment protocols aimed at this neuroinflammatory process.
2) Isiosyncratic reaction to the venously administered tracer [18F]DPA-714 is
not rendered likely. [18F]DPA-714 has been used in humans in previous studies
and no negative effects have been reported with the use of dosis as described
in these studies. 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 250 ml blood will be withdrawn during the total PET
procedure and screening. Subjects will be excluded if the have donated blood or
lost a significant amount of blood in the four months prior to de PET scan.
Besdies, subjects are advised not to donate blood within three months after the
PET scan.
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.