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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Intervention
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, 35 slices/3.0 mm, TR = 2.0 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.
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, Stroop Color-Word Test, Trail Making Test, Verbal Fluency Test,
Digit Symbol Test, Wechsler Memory Scale, PASAT, Fepsy Finger Tapping. 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
appropriate) and type of menopause (natural or artificial), previous use of
hormone replacement therapy, psychological distress (Hopkins Symptom
Checklist), health related quality of life (EORTC QLQ-C30), self-reported
cognitive problems (MOS questionnaire), self-reported medical history and
medication use.
For the women treated with chemotherapy the following additional information
will be obtained through the medical records: kind of cytotoxic treatment,
radiotherapy yes/no, endocrine therapy yes/no. For the breast cancer patients
not treated with chemotherapy, the following information will be obtained
through the medical records: radiotherapy yes/no, endocrine therapy yes/no.
To study possible mediating effects of stress on the relation between
chemotherapy and cognition, cortisol levels will be measured in hair samples.
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.
Except for saliva sampling, all parameters will be measured during both
assessments.
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. 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:
1. Delineate a more specific neurotoxicity profile by studying brain activity
with functional MRI during performance on tasks that are specifically sensitive
to executive function and memory.
2. Investigate anatomical changes in order to clarify underlying mechanism(s)
by performing structural and chemical MR imaging.
Study design
This prospective study with an observational design 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
Study burden and risks
All subjects will be tested twice, after surgery and before subsequent therapy
and a year after completion of chemotherapy, or at yoked time intervals. Each
test assessment will last two and a half hours and consists of a
semi-structured interview, several questionnaires and neuropsychological tests,
a practice session, and an MRI scanning session of one hour. During 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.
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 (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.
During both assessments, a small sample of hair will be collected to allow
analysis of cortisol levels (see attached file with instructions about hair
sampling). During interviews, patients indicated not to have any specific
concerns regarding this measure. In addition, saliva samples will be taken
during the first assessment 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.
No information regarding individual performance, findings on individual
cortisol measures or DNA analyses will be given in a standard way. All subjects
will be given the opportunity to be informed about overall results of the
study.
plesmanlaan 121
1066 CX Amsterdam
NL
plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
All groups:
-female, independent of menopausal status
-age under 70 years (to allow use of the same neuropsychological test battery)
-sufficient proficiency in the Dutch language;Experimental group:
-newly diagnosed breast cancer patients without distant metastases who will receive anthracycline-based chemotherapy ;Breast cancer control group:
-newly diagnosed breast cancer patients without distant metastases who do not require chemotherapy;Healthy control group:
-healthy females, matched for age
Exclusion criteria
All groups:
-previous malignancies
-excessive use of alcohol or drugs
-use of psychotropic medication
-neurologic or psychiatric disorders that may influence cognitive functioning
-conditions that preclude MRI examination.;Experimental group and breast cancer control group:
-relapse and/or metastases
- treatment with trastuzumab (Herceptin)
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 | NL32148.031.10 |