Effects of fingolimod on functional brain adaptation and clinical measures in multiple sclerosis

Physical problems as well as cognitive impairment are frequently seen in
patients with multiple sclerosis (MS). Currently, no effective treatment is
available to alleviate these disabling symptoms. Important new insights into
the pathophysiology of MS cognitive impairment have been gained, which are
consistent with a *functional reorganization model*. This model implies that
cognitive impairment is preceded by reorganization of brain function (as
measured with functional magnetic resonance imaging (MRI)) and is regarded as a
crucial compensatory mechanism that counterbalances on-going brain damage and
delays the onset of MS cognitive decline. Recently, the first oral
immunomodulating treatment, fingolimod (gilenya), has been introduced in the
field of MS and has shown to be effective in terms of disease activity in
relapsing remitting (RR) MS patients. Additionally, animal studies show that
fingolimod might have a neuroprotective effect. To date, it is not yet known
whether fingolimod has a positive effect on cognitive functioning and
functional reorganization of RRMS patients.

The main objective of the proposed study is to investigate whether the
disproportionally strong clinical effects of fingolimod in RRMS can be
explained by enhanced functional brain adaptation and whether enhanced
functional adaptation is sustained over time. Functional brain adaptation will
be measured with task-related brain activation (during information processing)
and resting-state functional connectivity. We will investigate the effects of
enhanced functional adaptation on cognition, disability and progression.

The proposed study is a prospective, single-center, interventional,
longitudinal patient-control study assessing the effect of fingolimod on
cognition and functional brain adaptation in RRMS patients.

Subjects will visit the outpatient clinic 3 times in a period of 18 months for
various measurements: neurological examination (patients only), extensive
neuropsychological testing, structural and functional MRI and blood sampling.

MRI, neuropsychological testing and blood sampling.

All patients need three visits at the outpatient clinic of VU University
medical center for neurological examination (patients only; approximately 30
min.), neuropsychological testing (approximately 60 min.), MRI scanning
(approximately 60 min.) and blood sampling. Prior to the visit, subjects are
asked to fill out 4 questionnaires (approximately 30 min.). The baseline
measurement for patients is prior to the start with medication. Follow-up
measurements will be 6 and 18 months after the baseline measurement.

The treatment of patients will not be changes by this study (i.e. standard of
care). Additionally, the decision to start with first line therapy or
fingolimod is made by the patient and treating neurologist, and is not
influenced by this study. Therefore, the intervention only consists of
neurological examination, neuropsychological examination, MRI scanning and
blood sampling. These measurements are risk-free: MRI is a safe technique, and
subjects will be screened for safety criteria to undergo MRI scanning (and
earplugs will be provided to reduce scanner noise). Side effects due to
medication are not directly related to the present study.