[LONGPDE10] Follow-up measurement of brain phosphodiesterase 10 A (PDE10A) enzyme levels in Huntington*s disease gene expansion carriers, 18 to 28 months after initial PET measurement in CHDIKI1201/PET-HD-PDE10A

Huntington*s disease (HD) is a neurodegenerative disorder characterised by
progressive loss of the medium-sized spiny neurons in the striatum and by the
development of chorea, psychiatric symptoms and cognitive deficits. The
disorder is inherited as autosomal dominant disease and is characterised by the
expansion of the CAG (codon that codes for the amino acid glutamine) repeat
beyond the normal 10-35 repeat range in the IT15 gene encoding for the protein
huntingtin . The hallmark of the disease is the accumulation of aggregates of
mutated huntingtin, which has been found to impair cyclic adenosine
monophosphate (cAMP) signalling and gene transcription mediated by the cAMP
responsiveelement binding protein (CREB) . Phosphodiesterase 10 A (PDE10A) is
an enzyme which is highly enriched in the medium-sized spiny neurons of the
striatum and has an important role in the regulation of cAMP and cyclic
guanosine monophosphate (cGMP) levels. Target genes of CREB include those
responsible for neurotransmitter synthesis, release and signalling pathways ,
and also the brain derived nerve factor . Inhibition of PDE10A by inhibitors
such as TP10 has been found to decrease neurodegenerative changes in the
striatum of animal model of HD and restore cAMP dependent CREB signalling , .
In animal models of HD it has also been found that changes of the levels of
PDE10A occur also before the onset of motor dysfunction , suggesting that in
Huntington*s Disease Gene Expansion Carriers (HDGECs) this abnormality can be
present even before neurodegenerative changes take place and before the onset
of clinical symptoms. Reduced levels of PDE10A messenger ribonucleic acid
(mRNA) and protein have been found also in homogenates from the striatum of
HDGECs . Inhibitors of PDE10A are now under clinical investigation for
application in schizophrenia and might also be useful for the treatment of HD
in which psychiatric symptoms also are prevalent.
In vivo imaging of PDE10A is at present possible using positron emission
tomography (PET). A recent study with the PDE10A radioligand [18F]JNJ42259152
has reported a statistically significant difference in enzyme availability in
HD patients compared with controls by 71% in the caudate and by 63% in the
putamen (10). [18F]MNI-659 is a radioligand for PDE10A developed at Molecular
Neuroimaging; their recently published data in a small cohort of 11 HDGECs
suggest that [18F]MNI-659 has the potential to serve as a striatal imaging
biomarker (11). Initial data from the study CHDIKI1201/PET-HD-PDE10A show that
the PDE10A enzyme is markedly affected in stage 1 and in late pre-manifest
HDGECs (12). In stage 1 HDGECs compared to controls, striatal volumes, dopamine
D2 receptor (D2 receptor) and PDE10A availability were 62±5%, 62±12%, and
21±33% of age-related control values (p<0.05). In late pre-manifest HDGECs
compared to controls striatal volumes, D2 receptor and PDE10A availability were
80±18%, 72±12% and 53±22% of control values (p<0.05, except for nucleus
accumbens volume). The REGISTRY study is a European study collecting
prospective data on the phenotypical characteristics of HDGECs and individuals
that are part of an HD family. The aims of the REGISTRY study are to
investigate the course of the disease, genetic factors, and biomarkers.
REGISTRY can also facilitate identification and recruitment of HDGECs to
clinical studies and trials. The REGISTRY study is performed by the European
Huntington*s
Disease Network (EHDN). A similar observational study to REGISTRY, by the name
of ENROLL-HD has been set up with a more global reach than REGISTRY. ENROLL-HD
has similar aims to REGISTRY and sites are currently being transferred one by
one from REGISTRY to ENROLL-HD as they are granted appropriate ethical and
other necessary approvals. It is anticipated that HDGEC recruiting sites on
this study may transfer to ENROLL-HD during their participation in the study.
The HDGECs recruited into this study will therefore have completed the previous
PET study CHDIKI120/PET-HD-PDE10A and will be participating in either the
REGISTRY or ENROLL-HD study. CHDI is the funding organization for the REGISTRY
study and the sponsor for the ENROLLHD study.

The primary objective is to measure the longitudinal changes of PDE10A enzyme
availability in the caudate, putamen, and globus pallidus of Huntington*s
Disease Gene Expansion Carrier (HDGECs) by comparison of the follow-up and
initial Positron Emission Tomography (PET) measurements.
The secondary objectives are to:
1) Examine the correlations between longitudinal changes of [18F]MNI-659
binding potential (BPND) and longitudinal changes of clinical parameters
2) Compare the longitudinal changes of [18F]MNI-659 BPND between all HDGECs
stages studied.

The study will be a follow-up, examining HDGECs at different stages of the
disease (early and late pre-manifest, stage 1 and stage 2).The follow up PET
measurement can be performed from 18 to 28 months after the initial PET
measurement, with the aim of performing the follow-up PET measurement between
18-20 months after the initial PET measurement. The HDGECs (pre-manifest and
manifest) included in this study will be recruited from the subjects that
completed study CHDIKI1201/PET-HD-PDE10A. There will be a maximum of 45 HDGECs
in the study.
The HDGECs will perform 2 study visits; Visits 1 (screening) and Visit 2 (PET)
and 2 telephone follow ups, one after Visit 1 (telephone follow-up after
screening) and one after Visit 2, (telephone follow-up after PET) during a
maximum of 97 days.
The study will be conducted at the same recruiting centres in 4 recruiting
countries for HDGECs (Sweden, Denmark, Norway, and the Netherlands) which
participated in study CHDIKI1201/PET-HD-PDE10A.
There is one imaging centre: KI PET Centre, Stockholm, Sweden.

The radioligand [18F]MNI-659 will be administered at doses less than 5
micrograms, within the microdosing concept, and no pharmacological effects are
expected. As of 31 October 2014 in study CHDIKI1201/PET-HD-PDE10A [18F]MNI-659
has been administered to 18 healthy controls, and 27 HDGECs at the PET Centre,
Karolinska University (KI) Hospital, SE-171 76 Stockholm, Sweden, without any
safety concern. In this study the injected radioactivity of [18F]MNI-659 will
be similar to the baseline assessment, namely 185 MBq/70 kg of body weight
±10%. The effective dose for the injection of [18F]MNI-659 is approximately 5.6
mSv (approximately 2 years of background radiation in Sweden) for an average
person weighing 70 kg. The total cumulative radiation dose the HDGECs will
receive over 18-28 months (i.e. the interval between the initial PET
measurements with [11C]raclopride and [18F]MNI-659 and the follow-up
PETmeasurement with [18F]MNI-659) will be approximately 14 mSv (approximately
4-5 years of background radiation in Sweden). Although the life expectancy of
an HDGEC can be several years or decades, particularly in case of pre-manifest
subjects, the risk associated with such a cumulative radiation dose is
acceptable, justifying the study in view of the progressive and devastating
nature of this fatal disease that currently has no cure or therapy that could
halt the progression and modify the disease. There will be no direct benefit to
subjects participating in this study. However, this study can provide important
information that could be applied to the ongoing development of PDE10
inhibitors in HD and result in an immediate impact on the development of a
potential treatment. In addition the results of the longitudinal study could
help further understand
PDE10A enzyme involvement in HD and validate PDE10A PET imaging as a suitable
biomarker for future clinical trials in HD.
Though PET imaging itself causes no pain there may be some discomfort from
having to remain still during the scanning. Claustrophobic subjects may feel
some anxiety while being scanned.