Clinical follow-up on the development of impulse control disorders in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that is associated
with progressive degeneration of dopaminergic neurons (Groenewegen et al.
1997). Apart from the characteristic motor symptoms such as bradykinesia,
rigidity, tremors and postural instability, PD is also associated with
neuropsychiatric symptoms such as depression, anxiety and impulse control
disorders (ICD) (Aarsland et al. 2012). The neuropsychiatric disorders often
have a higher impact on the quality of life than the motor symptoms (Mamikonyan
et al. 2008). The prevalence of ICD in PD is approximately 14% (Voon et al.
2011). ICD enclose a spectrum of disorders that show commonalities with
obsessive-compulsive and related disorders and substance use disorders (van den
Heuvel et al., 2010). ICD are frequently described as behavioral addictions in
which patients no longer have the ability to suppress an impulse, drive or urge
that is potentially dangerous to the patients themselves and/or their
surrounding (American Psychiatric Association, 1994; van den Heuvel et al.,
2010). Examples of ICD include compulsive shopping, compulsive eating,
pathological gambling, hypersexuality, punding and dopamine dysregulation
syndrome (van den Heuvel et al. 2010; Voon et al. 2011). Risk factors
associated with ICD in PD are young age, an early disease onset, male gender,
depression, novelty-seeking personality traits and a positive (family) history
of substance abuse (Voon et al. 2009; Wu et al. 2009). ICD seldom occur on
their own in PD but seem to be a consequence of dopamine replacement therapy,
mainly dopamine agonists (van den Heuvel et al. 2011; Voon et al. 2011).
Dopaminergic projections from the ventral tegmental area have an important
neuromodulatory role in the limbic fronto-striatal circuit that connects
cortical areas, such as the anterior cingulate cortex and orbitofrontal cortex
with the ventral striatum, i.e. caudate nucleus and nucleus accumbens
(Groenewegen et al. 1997; Groenewegen and Trimble 2007; Leh et al. 2007; Haber
and Calzavara 2009). The ventral striatum seems to have an important role in
the pathophysiology of both depression and ICD in PD (Voon et al. 2011; Vriend
et al. 2013; Vriend et al. 2013) and is also involved in the initiation of
addictive behavior (Everitt et al. 2008). In a recently published review we
describe a model in which degeneration of mesolimbic dopamine projections from
the ventral tegmental area towards the ventral striatum can directly result in
symptoms of depression. Degeneration of ventral striatal dopaminergic
projections combined with dopamine replacement therapy could subsequently lead
to the disturbance of reward-related processes and could in that way lead to
the development of ICD. This model is corroborated by studies, including those
from our own research group, that show that depressive symptoms as well as ICD
symptoms are associated with reduced striatal dopamine transporter (DaT)
availability (Weintraub et al. 2005; Rektorova et al. 2008; Hesse et al. 2009;
Cilia et al. 2010; Lee et al. 2013; Voon et al. 2013; Vriend et al. 2013;
Vriend et al. 2013). DaT availability, measured with a SPECT scan, is an in
vivo marker for the integrity of dopaminergic projections. Nevertheless,
studies on the association between ICD and DaT availability were conducted in
relatively small sample sizes. Moreover, to our knowledge no prior study has
investigated the course of neuropsychiatric symptoms in a PD patient cohort for
an extended period of time; from diagnosis and the start of dopamine
replacement therapy until four years into the disease. Our study design also
allows us to investigate the (temporal) relation between the symptoms of ICD,
depression and anxiety, something that has so far received little scientific
attention.

If our previous results of reduced striatal DaT availability in PD patients
with ICD symptoms are confirmed, DaT SPECT scans can in the future be utilized
to screen PD patients on their predisposition and risk to develop ICD after
commencing dopamine replacement therapy. These patients can thereafter receive
a distinct treatmentplan to avoid the development of these symptoms. We expect
that patients that develop an ICD after commencing dopamine replacement therapy
will exhibit reduced DaT availability at baseline compared with PD patients
that do not develop an ICD and will also show higher incidences of symptoms of
depression and anxiety. Furthermore, we are interested in the relation between
these neuropsychiatric symptoms (ICD, depression and anxiety) and cognitive
functioning, most notably executive functioning. Although it has previously
been found that executive functioning is disturbed in patients with ICD but
without PD (Goudriaan et al. 2004), no study has yet investigated this in PD.

the primary aim of this research is to investigate whether the development of
ICD in PD after commencing dopamine replacement therapy can be predicted with
baseline DaT availability. We also want to look at the (temporal) relation
between the symptoms of ICD and deficits in impulsivity, executive functioning
and de presence of symptoms of depression and anxiety.
The results of this study can contribute to:
1) a better understanding of how the DaT SPECT scan, that is often acquired as
part of the diagnostic process, can be used in the clinic to help determine
what the risk is of developing ICD in PD patients prior to commencing dopamine
replacement therapy. This is relevant for the type of dopamine replacement
therapy that is prescribed and/or the intensity of routine psychiatric
evaluations.
2) insight into the course of, and the temporal relation between the symptoms
of ICD, anxiety and depression to allow the formulation of a more effective
(and simultaneous) treatment for these frequently co-occuring neuropsychiatric
symptoms in PD.

Follow-up on medication-naive Parkinson patients from which a SPECT scan was
acquired at baseline as part of the diagnostic process with a
[123I]N-*-Fluoropropyl-2*-carbomethoxy-3*-(4-iodophenyl)nortropane
([123I]FP-CIT) tracer that binds to the dopamine transporter (DaT). These
patients are subsequently prescribed dopamine replacement therapy. Follow-up
measurements are acquired at six months, 1 year, 2 years and 4 years after the
DaT SPECT scan. The follow-up measurements will be planned as close as possible
to the ideal date, which will be defined from the date of day screening. A
maximal deviation of a month from this ideal date will be utilized. At each
timepoint patients are asked to fill out a number of questionnaires that
determine the presence and severity of neuropsychiatric symptoms (ICD,
depression, anxiety). The frequency and the duration of the follow-up
(measurements) has been chosen in such a way that it maximizes the detection of
ICD symptoms. The average latency for developing ICD symptoms after commencing
dopamine replacement therapy was in previous research 11.4 months (Vriend et
al. 2014), although other research shows that there is al lot of
inter-individual variability and ranges from a few months to several years
(Bastiaens et al. 2013). Moreover, the duration of our follow-up also allows us
to study the course of the symptoms of depression, anxiety and impulsivity and
cognitive functioning during a longer period of disease progression.

In this observational study only questionnaires and computertasks are added to
the regular treatment of Parkinson's disease. There's no intervention. The
study has been classified as 'negligible risk' since we do not expect any
adverse effects of filling out questionnaires and executing (computer)tasks
which, for the most part, are also performed as part of routine clinical care.
In a period of four year subjects are asked to visit the outpatient clinic of
the VU University medical center four times.At one timepoint patients are asked
to fill out questionnaires at home and post it back. If patients perceive the
burden of traveling to the hospital as too high, the measurements can also be
performed in the patients home. Every visit to the VU University medical center
will take approximately one to two hours. the total time investment for all the
visits sums up to eight hours in a period of four years. The burden for
patients is therefore quite low. To further decrease the burden we will try to
schedule the visits so that they are on the same day as the regular outpatient
visits or perform the measurements at the patient's home.