In our recent studies we found indications of the existence of particular cognitive deficits as well as memory impairments following different regiments of cytostatic agents. Together with the indications form our animal studies of a potential…
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Brief title
Condition
- Cognitive and attention disorders and disturbances
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Research involving
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Outcome measures
Primary outcome
MRI scanning will be performed using a Philips Intera 3.0 Tesla scanner with an
eight channel Sense head coil. MRI imaging parameters:
1. 3-dimensional T1-weigthed sequences followed by (automated) volumetric
measurement, as a gross measure for tissue loss.
2. FLAIR sequence to determine presence and extent of demyelination.
3. MR spectroscopy allows the safe in vivo measurement of brain neurochemistry.
Compounds that can be identified are N-acetylaspartaat (NAA), choline (Cho) en
myo-inositol (MI). NAA is contained almost exclusively within neurons and is
considered a neuronal marker for neuronal density and viability. Cho indicates
integrity of neuronal structure. MI reflects glial content.
4. Diffusion Tensor Imaging (DTI) will be used to study the (density) of fibers
subserving well-defined functional networks and as such provide an index of
damage in the normal appearing white matter. The outcome measures will be used
to study correlations with specific functional deficits.
5. Functional MRI: EPI sequence, 38 slices/2,5 mm, 0,5 mm slice gap, TR = 2.1
s, axial sequence acquisition. We will use the following, well-studied
paradigms measuring executive functioning and memory to investigate changes in
the blood oxygen level dependent (BOLD) response, reflecting neural activity.
Tower of London task: a task widely used to investigate executive/planning
processes and known to robustly activate the dorsolateral prefrontal cortex.
Flanker task: previous studies by our group consistently show impaired
performance on this task by patients treated with chemotherapy. It provides a
means for examining interference control processes. Activation of the anterior
cingulate cortex (a central component of the neural circuit for action
monitoring) is reliably observed during this task.
Paired associates task: a task concerning implicit memory. The medial temporal
lobe (e.g. hippocampus) is reliably activated during encoding as well as
retrieval of stimuli.
Resting state: subjects will be instructed to lie still, while no specific
cognitive task is presented. These so-called resting state data contain
information about several well-known brain networks, as well as the default
mode network, which is thought to reflect baseline activity of the brain.
Heart rate and respiration will be recorded during this scan and will be used
as regressors in our analyses, to take into account the effect that speed of
respiration and heart rate has on signal changes in BOLD response.
Secondary outcome
In addition to the tests that are administrated while MRI scans are being
acquired, the patients will also be tested with a neuropsychological
examination. The neuropsychological tests will take place before the MRI
scanning session.The neuropsychological examination will consist of the
following classical neuropsychological tests, which were also included in
previous neuropsychological examinations conducted at the NKI-AvL: Hopkins
Verbal Learning Test, Trail Making Test, Verbal Fluency Test, Digit Symbol
Test, Wechsler Memory Scale, Fepsy Finger Tapping, Flanker task, Behavioural
Assessment of the Dysexecutive Syndrome - zoo-map, Digit span, Visual Reaction
time task. These tests are included to obtain information on the current
cognitive status of the participants.
The following data will be collected for all participants: Age, educational
status, smoking habits, alcohol intake, body mass index, age at menopause (if
applicable) and type of menopause (natural or artificial), previous use of
hormone replacement therapy, psychological distress (Hopkins Symptom
Checklist), current mood state (Profile Of Mood States), health related quality
of life (EORTC QLQ-C30), self-reported cognitive problems (MOS questionnaire),
self-reported stress (Perceived Stress Scale), presence of Post Traumatic
Stress Disorder (PTSD) (Trauma Questionnaire), lifetime depression and PTSD
(Compositie International Diagnostic Interview (CIDI)) , self-reported
personality traits (TIPI), self-reported medical history and medication use.
For the women and men that underwent chemotherapy the following additional
information will be obtained through the medical records: kind of cytotoxic
treatment, radiotherapy yes/no, endocrine therapy yes/no (if applicable). For
the breast cancer and testicular cancer patients that did not undergo
chemotherapy, the following information will be obtained through the medical
records: radiotherapy yes/no, endocrine therapy yes/no (if applicable).
To study possible mediating effects of stress on the relation between
chemotherapy and cognition, cortisol levels will be measured in hair samples.
Through this method, cortisol levels can be measured for a period up to the
past six months. Earlier research suggested a dysregulation in
hypothalamic-pituitary-adrenal (HPA) axis responsiveness among breast cancer
survivors.
Recent studies have indicated a possible mediating role for specific genetic
polymorphisms, e.g. APOE, BDNF and COMT, in the development of cognitive
dysfunction following chemotherapy. Therefore, saliva samples will be taken to
screen for these genetic polymorphisms in relation to cognitive outcomes after
cancer treatment. Blood samples will be collected in all subjects to analyze
cytokine levels, e.g. IL1, IL6 and TNFα. In cancer patients, cytokines have
been shown to be increased. The deregulation of cytokines has been associated
with neurotoxicity and deficits in cognitive performance following chemotherapy
. Blood samples will also be used to assess hormonal levels in the testicular
cancer patients. In males, lower endogenous testosterone-levels may be related
to cognitive dysfunction. It has been shown that chemotherapy in males may lead
to a greater risk of low testosterone levels.
Background summary
Over the last years, interest in cognitive deficits after chemotherapy has
increased. In several neuropsychological studies in breast cancer patients we
as well as others have found cognitive impairments after chemotherapy. In a
series of neurophysiological studies we also found abnormalities in EEG
measures in this patient population. A recent study by our group showed
converging evidence for neurocognitive problems based on neuropsychological and
neurophysiological measures and self-report of cognitive complaints up to five
years after cessation of treatment with chemotherapeutic treatments. In
addition, our animal studies have demonstrated long-lasting dose-dependent
decreases in cell proliferation in the hippocampal formation in rats, after
single intravenous administration of methotrexate and other cytostatics.
Despite these indications of long-lasting effects on the central nervous
system, resulting in persistent cognitive impairment, our understanding of the
nature and the mechanism(s) driving this compromise is fragmentary at best.
Study objective
In our recent studies we found indications of the existence of particular
cognitive deficits as well as memory impairments following different regiments
of cytostatic agents. Together with the indications form our animal studies of
a potential contributory role of reduced neurogenesis in the hippocampus and
the promising results of our pilot data, compelling arguments are provided to
initiate a study aiming to:
- Investigate the late effects of chemotherapy on neuropsychological
performance, and MRI brain function and structure in patients that received
standard-dose chemotherapy for breast cancer or testicular cancer compared to
disease specific and healthy controls.
In breast cancer survivors, there will be also investigated whether there are
difference in cognitive impairment between high-dose (from a pilot study from
our group (PTC07.0766)and low-dose chemotherapy. By including testicular cancer
survivors, we can investigate whether memory impairments also occur following
different regiments of cytostatic agents.
Study design
This crossectional study is a collaboration between the department of
Psychosocial Research and Epidemiology and the department of neuro-oncology of
the NKI-AvL and the department of Radiology of the Academic Medical Center.In
this study, patients from the NKI-AvL, VU medical center (VUmc), Daniel den
Hoed Kliniek and Leids University Medical Center (LUMC) will be included.
Study burden and risks
Participants will be tested once. The test assessment will last three hours and
consists of a semi-structured interview, several questionnaires, several
neuropsychological tests, and an MRI scanning session of one hour. Half of the
scanning time, the patient is actively engaged in task performance. The other
half of the time, MR sequences are acquired for which no active involvement of
the patient is required.
During the MRI scans, the patient has to lie still in the scanner which is
sometimes considered inconvenient. Moreover, the scanner produces noise, which
is effectively reduced by the use of earplugs and headphones. When standard
safety rules are applied (e.g., no ferromagnetic objects inside the scanner
room) no risks exist for the patient. Ample experience with patient populations
have indicated that this procedure is feasible and is not considered too
burdensome. Feasibility of this assessment was also demonstrated in a pilot
study (PTC07.0766)2 by our group, where all participants finished all
measurements. This study is similar to this pilot study except for the
inclusion of testicular cancer patients. Furthermore, a prospective study in
breast cancer patients of our group has recently been approved (PTC10.1229),
which method is also highly similar to this study.
During assessment, a small sample of hair will be collected to allow analysis
of cortisol levels (see attached file with instructions about hair sampling).
We interviewed a random sample of patients visiting the chemotherapy day-care
unit. Patients indicated not to have any specific concerns regarding this
measure. Blood will be collected to allow for analyses of hormonal levels as
well as cytokines which may play a mediating role in neurotoxic effects of
chemotherapy. In addition, saliva samples will be taken to allow for genetic
screening for factors related to cognitive functioning. Oral collection of
saliva is a non-invasive and easy way to collect specimen for genetic analysis.
Finally, some blood will be taken by an experienced and certified investigator,
which should not be burdensome.
No information regarding individual test performance, MRI findings (except for
incidental findings) and findings on individual cortisol measures will be
communicated to participants. The assessments will take place at the Academic
Medical Center of the University of Amsterdam (AMC), because of functional MRI
facilities at that site. Travel expenses and parking costs will be reimbursed.
To allow for a short break during the assessment, patients will be given a
lunch voucher.
plesmanlaan 121
1066 CX Amsterdam
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plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
All groups:
- sufficient proficiency in the Dutch language
- age under 70 years (to allow use of the same neuropsychological test battery)
- eligibility to undergo the MRI scanning session;Cross sectional part, experimental group:
- previous participation in our neuropsychological study
- having been treated with standard-dose chemotherapy (FEC) ;Cross-sectional part, control group
- previous participation in our neuropsychological study
- No treatment with chemotherapy ;Control group:
- Healthy subjects need to be matched for age
Exclusion criteria
- metastatic disease or relapse since previous neuropsychological examination
-history of neurological or psychiatric signs that can impact cognitive functioning
- alcohol or drug abuse
- conditions that preclude MRI examination
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL33374.031.10 |