Frontotemporal dementia Imaging of Neuroinflammation, Degeneration and Microglia-Related Effects

Frontotemporal dementia (FTD) is the second most common early onset dementia (<
65 years), comprising various clinical, genetic and pathological subtypes. The
age of onset, clinical presentation and disease course vary considerably, even
within the same genetic or pathological subtype, which is largely unexplained
until now. An emerging hypothesis is that neuroinflammation plays a role in the
variability in clinical onset, clinical presentation and disease progression in
FTD. Increasing evidence from cellular, animal, and human postmortem studies
points towards the involvement of microglia in the pathogenesis of FTD.
However, only few studies have investigated microglial activity in vivo in FTD.
Microglia can be visualized using PET imaging, specifically targeting markers
of neuroinflammation such as the 18-kDa translocator protein (TSPO) receptor.
The most widely used tracer for TSPO imaging so far has been the [11C]PK11195
tracer. The accuracy of this tracer is, however, limited due to poor
bioavailability in the brain and low binding specificity for activated
microglia. The second-generation tracer [18F]DPA-714 has improved
bioavailability and binding specificity in the brain compared to [11C]PK11195,
thus enabling a more accurate quantification of microglial activity. Due to
these favorable properties, this tracer has been increasingly used for
microglial imaging in clinical studies. The novel TSPO [18F]DPA-714 tracer has
given promising results for the quantification of microglial activation in
other neurodegenerative diseases, such as Alzheimer*s disease, multiple
sclerosis and amyotrophic lateral sclerosis. To our knowledge, this tracer has
never been used in FTD.
Our hypothesis is that in vivo imaging of microglia with the [18F]DPA-714
tracer will enable to visualize patterns of microglial activation in patients
with FTD and to correlate them with clinical features and other disease markers
(MRI measures, blood/CSF biomarkers, symptomatology, neuropsychological
scores). This may help to better understand the role of microglia in the
pathophysiology of FTD and onset of clinical disease, and to determine whether
[18F]DPA-714 may be used as a diagnostic tool in FTD.

Our primary objective is:
i. To assess the quantity and regional distribution of [18F]DPA-714 binding as
a marker of microglial activation in patients with FTD compared to controls.

Our secondary objectives are:
i. To compare the quantity and regional distribution of [18F]DPA-714 binding in
symptomatic and presymptomatic carriers of FTD genetic mutations;
ii. To explore the relationship between [18F]DPA-714 binding, clinical
presentation and progression, and other markers of neurodegeneration (MRI,
CSF/serum biomarkers).

We will perform a cross-sectional, observational study where individuals will
undergo a diagnostic intervention, consisting of a single PET-MRI scan using
the TSPO tracer [18F]DPA-714. The expected total duration of the project is two
years; the project will last until the completion of the study procedures for
the expected study sample.
Participants will be recruited from the Dutch FTD-RisC study cohort, which
includes more than 150 at-risk subjects from families with MAPT, C9orf72, GRN
or TARDBP gene mutations. Additionally, we will invite sporadic FTD patients to
participate in this study. These are patients that have been seen at the
Alzheimer Center of the Erasmus Medical Center.
For the current study, individuals that are eligible will first undergo genetic
screening to genotype the rs6971 polymorphism of the TSPO gene. This will
enable us to determine binding affinity for the tracer. Next, high- and
medium-affinity binders will be invited to undergo a single [18F]DPA-714
PET-MRI scan at the Erasmus Medical Center on a clinical PET-MRI scanner (GE
Healthcare). All subjects will be required to sign informed consent prior to
participation.
All patients will have a follow-up visit one year after the [18F]DPA-714
PET-MRI scan.

The overall risk associated with the study is estimated as low, and sufficient
measures will be taken to deal with potential difficulties experienced by the
participants. Idiosyncratic reactions to the tracer are unlikely. Pre-clinical
testing of the tracer points to a favorable safety profile and a high margin of
safety. Only mild transient side effects are observed in rats at doses 125
times higher than the maximal intended human dose. Further, other clinical
studies used this tracer in humans successfully and reported no adverse
effects. To deal with potential adverse effects during or directly after the
scan, a physician will be present during the scanning procedures and will
intervene if necessary. Further, in case of adverse effects occurring later,
participants will be asked to contact a reference person among the
investigators, and will receive the necessary medical help. The risks
associated with the scanning procedures are rare and of minor severity. The
radiation exposure is within acceptable limits. The scanning procedures may
result in local side effects at the site of injection (e.g. pain, local
hemorrhages, bruising, infection or blood clots), and in discomfort of the
participants during the scan. Local side effects, if brought to medical
attention, will be treated by a nurse or a physician as appropriate. The scan
will be conducted with respect and care for the patient; the staff will provide
clear instructions and support to make the participant at ease. If requested by
the participant, the scanning procedures will be interrupted. An additional
uncertainty is the possibility of incidental findings in the images. Incidental
findings will be assessed by a competent clinical team to determine the
clinical relevance. Clinically relevant findings will be communicated to the
participant by his/her family physician.
The overall low risk is deemed acceptable when considering the expected
benefits of the study, i.e. the discovery of important disease mechanisms that
may lead to better diagnostics and therapeutic options targeting
neuroinflammation in the patient population with FTD. FTD is a fatal disease,
for which no cure is available. This is partly related to incomplete knowledge
about disease mechanisms of neurodegeneration, and to the lack of reliable
biomarkers to track disease activity and predict the underlying pathology,
which are needed to select patients for therapeutic trials. With this in mind,
the current study attempts to expand the current state of knowledge on FTD
pathogenesis, and to test [18F]DPA-714 PET as a potential diagnostic tool and
disease biomarker.