FDG-PET imaging in idiopathic REM-Sleep-Behaviour Disorder (RBD)

Movement disorders or neurodegenerative brain diseases in general are difficult
to diagnose at early disease stages. One reason for this is the slow
development (years) of such conditions with only few complaints or unclear
signs at the beginning. Well-known examples of these diseases are Parkinson*s
disease (PD) and Alzheimer*s disease (AD). But there are many more less
frequent conditions as well. An accurate diagnosis as early as possible is
however necessary to avoid superfluous further procedures or unjustified
treatments and, most importantly, to begin with potential protective
therapeutic strategies as they may emerge in the course of time. A correct
diagnosis is equally important to reliably inform the patient about his
condition and to anticipate prognostic actions.
Sophisticated neuroimaging methods of the brain provide an inroad into this
problem in that they can detect pathological changes in the brain pertinent to
the group of diseases investigated here. Structural scan methods like X-ray CT
and MRI scans are not helpful in early disease stages since at that stage no
clear anatomical changes can be noticed apart from slight to moderate global
atrophy. At later stages some diseases may show structural abnormalities in
some of these conditions. But by that time the clinical picture is usually
already clear.
Radiotracer PET scans on the other hand can reflect regional brain biochemical
activity depending on the type of tracer applied. The PET tracer
[18F]-fluorodeoxyglucose (FDG) allows the measurement of regional cerebral
metabolic rate of glucose. FDG is a glucose analogue with physiological aspects
almost identical to glucose. It is transported from the blood to the brain by a
carrier-mediated diffusion mechanism. Glucose is then phosphorylated to
glucose-6-PO4 , and FDG to FDG-6-PO4 , catalyzed by hexokinase. While glucose
phosphate is metabolized further to carbon dioxide and water, FDG phosphate is
not a substrate for any enzyme known to be present in brain tissue, and is
trapped for some longer time and therefore a useful imaging marker of the first
step of the glycolysis.
In neurodegenerative brain diseases, specific brain regions degenerate with the
characteristic consequence of specific patterns of altered metabolic brain
activity. This happens before clear structural changes can be detected with
imaging techniques. Measurement of glucose consumption with FDG PET imaging
thus allows us to identify disease-specific cerebral metabolic brain patterns
in several neurodegenerative brain diseases at an early disease stage.
Several methods have been used to identify these metabolic brain patterns.
First, univariate methods like voxel-based statistical parametric mapping (SPM)
were used to identify group differences between patients with neurodegenerative
brain diseases and controls (1,2). However, Scaled Subprofile
modelling/principal component analysis (SSM/PCA), a multivariate method, not
only identifies group differences, but is also able to identify relationships
between relatively increased and decreased metabolic activity within different
brain regions in combined samples of patients and control scans (see Chapter 7
of this protocol *Statistical analysis*) (3,4). By using the SSM/PCA method,
metabolic disease-specific patterns have been developed for several
neurodegenerative diseases (5-7). In close collaboration with the New York
group of Eidelberg we have installed and operationalized the SSM/PCA method at
our department. This has resulted in the build-up of the GLIMPS project in
collaboration with various RUG and UMCG departments (Target, NeuroImaging
Center (NIC), Department of Nuclear Medicine and Molecular Biology, Department
of Neurology, and Neuroscience). In clinical practice we can now check each
subject for the metabolic patterns of multiple system atrophy (MSA),
progressive supranuclear palsy (PSP), PD and AD.
REM-sleep-behaviour disorder (RBD) is a parasomnia characterized by apparent
dream-enacting behaviours and loss of normal REM sleep muscle atonia (8). For
establishing the diagnosis, polysomnography (PSG) is required and represents
the clinical gold standard. RBD can be idiopathic, but is commonly associated
with neurodegenerative disorders characterized by α-synuclein deposition,
including PD, MSA and Lewy body dementia (DLB) (9,10). In a significant
proportion of cases, RBD occurs prior to the development of clinically evident
parkinsonism, and therefore idiopathic RBD may represent an early warning of
PD, MSA or DLB.
With idiopathic RBD being possibly an early feature of parkinsonism, and the
importance of an early diagnosis in parkinsonism, it is now possible to
investigate whether metabolic patterns are present in patients with idiopathic
RBD and if they could contribute to an earlier diagnosis.

The main aim of this study is to create a specific disease related pattern in
the patients with idiopathic RBD.

In this study 20 patients with idiopathic RBD and 20 gender- and age matched
healthy volunteers will be included.

After metabolic brain imaging, Statistical Parametric mapping (SPM8, functional
Imaging lab, London) and MATLAB (Mathworks, Sherborn, USA) is used for image
processing and statistical analysis. These image data will be used to explore
if it is possible to create a disease related pattern for RBD.

Both patients with RBD (or expected to have RBD) and healthy volunteers will be
recruited by means of advertisements in local newspapers and posters. Besides
these advertisements, patients with RBD will be recruited from referrals to the
University Medical Center Groningen. Voluntary written informed consent will be
obtained from each volunteer before performing any study-related procedures.
Each subject will be given both verbal and written information describing the
nature and duration of the study. The subjects will have two weeks to decide
about participation in the study. There will be an independent physician who is
available for further questions (Drs. J.J. de Vries). The subjects will not
incur direct costs by participating in the study.
After obtaining written informed consent all subjects will get an RBD-Screening
Questionnaire (RBDSQ) (see Appendix 1) (20). When it concludes a suspicion for
RBD (five or more questions answered with *yes*) they will get a
polysomnography, to validate the diagnosis of RBD. When they already have a
validated diagnosis of RBD (by polysomnography) the RBDSQ and polysomnography
will not be done again. When the RBDSQ concludes no suspicion for RBD, subjects
can participate as healthy volunteer.
When patients are diagnosed with RBD after the polysomnography, they will
undergo a neurological (by UPDRS I-III) and cognitive examination (MoCA). Also
healthy volunteers will undergo this neurological and cognitive examination.
Furthermore a smell test (Sniffin* Sticks Test or UPSIT - University of
Pennsylvania Smell Identification Test) and a colour test (Farnsworth-Munsell
100 hue Test) will be done with all subjects.
When subjects can be included they will undergo a FDG PET scan according to
protocol.

Risks in connection with FDG-scans or polysomnography are not known.
The time spent for the investigations is limited. The 15 hours polysomnography
is mostly performed sleeping.