Frontotemporal Dementia Risk Cohort (FTD-RisC): Early biomarker abnormalities in patients with frontotemporal dementia

Frontotemporal dementia and Alzheimer*s disease cause most of the dementia
cases in patients younger than 65 years. Often these diseases have insidious
onset, and differentiation between the two diseases in an early phase can be
difficult. With use of structural brain imaging such as magnetic resonance
imaging (MRI) loss of brain tissue can be seen but this may be present only
later in the disease process. Newer MRI techniques, such as resting-state fMRI
(rs-fMRI), Diffusion Tensor Imaging (DTI) and Arterial Spin Labeling (ASL) may
show altered patterns even before apparent brain tissue loss on conventional
imaging. In this project, we will study these patterns in patients with mild
FTD, AD and presymptomatic persons who carry a gene mutation leading to FTD or
AD. FTD can be caused by mutations in genes for microtubule-associated protein
tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72).
Early onset AD if often inherited in an autosomal dominant mode, linked to
genetic defects in the APP, PSEN1 and PSEN2 genes. For upcoming medication
trials, sensitive biomarkers to assess disease stage and track progression are
needed. In order to investigate the effect of FTD/AD causing mutations on
neural cells, neural cells can be derived from a skin biopsy (iPS cells). These
IPS cells can be compared between patients with a mutation, healthy mutation
carriers and persons without mutations. Subsequently, we can investigate the
effect of a potential disease-modifying agent.

The objective is to describe differences in MRI patterns in presymptomatic
mutation carriers, patients with mild dementia and controls. We will study
whether these patterns are specific depending on the type of dementia (FTD/AD)
or mutation (GRN/MAPT/C9orf72). In addition, we will study whether even before
clinical symptoms of dementia changes can be seen on MRI by investigating
presymptomatic carriers of genetic mutations causing FTD or AD. By means of
skin biopsy we can investigate the differences in neuronal cells. Furthermore,
we aim to find biomarkers in blood and cerebrospinal fluid e.g. with the use of
proteomics and miRNA techniques.

This is a longitudinal observational study over a period of five years with
baseline and two follow-up visits (in case of two-yearly visits) or four
follow-up visits (in case of yearly visits). Current participants will be asked
to continue their study participation for another five years; i.e. three visits
(in case of two-yearly visits) or five visits (in case of yearly visits). If
the participants consents, a skin biopsy and LP will be performed. The LP can
be repeated over time if the participant consents.

The participants will undergo fMRI scans and neuropsychological tests with no
known health risks. They will have these examinations annually or two-yearly in
a period of five years. They will have these examinations annually in a period
of maximum five years. There is no direct benefit for the participants, but
they will provide information on the most early brain changes occurring in
brains affected by dementia. As such, participation will lead to a better
understanding of the early phase of dementia. Future interventions will need to
be given in the earliest phases of the dementia process, at a time when brain
tissue loss is not severe. An adverse event of vena punction includes the
development of a hematoma. Adverse events of skin biopsy may include minor
bruising or local tenderness at the site of venous blood sampling. All
participants will be monitored to ensure proper hemostasis. There still is a
lot of uncertainty about the risk associated with lumbar punctures. Contrary to
popular belief, the risk is almost negligible. With the use of a thin,
non-traumatic, needle the risk of a headache, which is the most common
complication, is less then 10%. The quantity of liquor plays no role, as long
as it is not more than 30 ml. Other complications such as meningitis and
subdural spinal haematoma are very rare.