Prediction and recovery of cognitive impairment in neurosurgical patients.

A substantial (but unknown) number of patients, who are admitted for an
intracranial neurosurgical procedure (e.g., resection of a brain tumor or
microvascular decompression), already have cognitive deficits prior to surgical
treatment. Additional cognitive deficits may occur after surgery and even
persist for a prolonged period. Because cognitive functions are essential for
our daily social, occupational and personal life, is it important to have a
full understanding of factors that can predict cognitive functioning in
patients before and after surgery. In addition, subjective cognitive complaints
are among the most commonly reported complaints that physicians are confronted
with. To what amount these complaints need to be taken seriously and if they
have any diagnostic value or not, is not clear. Therefore, it is important to
get some insight into 1) predictors (sociodemographic, clinical, MR Imaging,
and (neuro)psychological variables) of objective cognitive functioning in
neurosurgical patients, 2) the incidence and severity of objective cognitive
impairments in neurosurgical patients before, and after surgery, and 3) into
the relationship between objective cognitive functioning and subjective reports
of cognitive functioning, fatigue, work status, work limitations, and community
integration (over time).
In addition, genetic factors, such as the alipoprotein E (APOE) polymorphism,
may be associated with a vulnerability to cognitive performance and
deterioration. The APOE gene codes for alipoprotein class E that, holds a
crucial position in (nerve) cell growth and repair within and outside the
central nervous system. The APOE *4 allel has repeatedly been shown to be
related to worse cognitive outcomes in other diseases (e.g., neurological
diseases, cancer) and in healthy elderly. Information on the role of APOE
genotype in cognitive status or change over time among patients with brain
tumors is lacking, although there are suggestions that this plays a role here
as well. If this proves to be the case, APOE genotype can be included as an
important additional predictor in our prediction models.

[Retrospective clinical path:
1) main objective: to identify predictors (sociodemographic, clinical, imaging,
and (neuro)psychological variables) of objective cognitive functioning of all
patients who undergo neurosurgyer, at 3 months after surgery
2) to describe the incidence and severity of cognitive impairment in these
patients before, and 3 months after surgical treatment

Additional from the prospective clinical path:
To evaluate the relationship between objective cognitive functioning (over
time) and subjective reports of cognitive functioning, fatigue, work status,
work limitations, and community integration.]

Predict sub-study:
1) main objective: to identify the predictors (sociodemographic, clinical,
imaging, and (neuro)psychological variables) of objective cognitive functioning
of meningioma and glioma patients before, and 3, 12, and 24 months after
surgical treatment
2) to describe the incidence and severity of cognitive impairment in meningioma
and glioma patients before, and 3, 12, and 24 months after surgical treatment
3) to evaluate the relationship between objective cognitive functioning and
subjective reports of cognitive functioning, fatigue, work status, work
limitations, and community integration (over time)

[HGG sub-study:
1) to determine the value of neuropsychological assessment versus MR Imaging in
predicting tumor progression in a subsample of patients with high-grade gliomas
2) to describe the incidence and severity of cognitive impairment in patients
with high-grade gliomas before, and after surgery
3) to evaluate the relationship between objective cognitive functioning and
subjective reports of cognitive functioning, fatigue, work status, work
limitations, and community integration (over time).

ApoE sub-study:
To retrospectively investigate the relationship between APOE genotypes,
specifically *4 carrier status, and
1) pre-surgical cognitive performance and
2) the cognitive course over time at 3 and 12 months after surgical treatment.]

Exploratory objectives
- to evaluate the applicability of the American norms of the test manual CNS
Vital Signs (computerized testbattery) in a Dutch control group and to evaluate
the sensitivity of CNS Vital Signs to detect cognitive impairment in
neurosurgical patients.

[The study is set up as a follow-up design to patients receiving intracranial
neurosurgical treatment. Patients complete preoperative (T0) and 3 months
post-operative (T3, T12) neuropsychological tests in the context of clinical
care. Data from this historical clinical group will be used retrospectively.
Patients who sign for informed consent fill out several questionnaires that
have been added to the clinical neuropsychological assessment for research
purposes, and therefore become part of the prospective clinical path. We aim to
include 400 patients in the prospective clinical path, in order to provide
sufficient numbers of patients that can be asked to participate in the predict-
or HGG sub-study.]

At least 12 months after surgery, at their post-treatment appointment, patients
will be asked to participate in (either) the predict (or the HGG sub-study,
depending on their histological diagnoses). Patients have two weeks to decide
whether they are willing to participate in the studies. If they sign for
informed consent, participants are followed up at (12 and) 24 months after
surgery (i.e, the predict sub-study) (or three-monthly starting 6 months after
surgery (T = 6, 9, 12, 15, 18, 2, 24) or until confirmation of progression of
disease by a threating physician (i.e., HGG sub-study)).
Data concerning demographic, medical/clinical, and (neuro)psychological
variables are collected at the follow-up assessments. [In addition, the HGG
sub-study uses data from the MR Imaging, which is performed pre-operatively,
and post-operatively every three months as part of the standard imaging
protocol.]

All neuropsychological assessments are scheduled as close in time to patients'
hospital visits (e.g. for MR Imaging) as possible.

[Retrospective ApoE-substudie: (1) perform genetic APOE-analyses on previously
collected, coded blood samples, (2) merge the coded data on the results of the
genetic APOE-analyses with the coded datafile of the neuropsychological
testdata and (3) conduct retrospective statistical analyses on the coded merged
file with genetic and neuropsychological data.]

In all studies, patients' cognitive performances are compared with those of
healthy controls, recruited from the general population matched for age,
gender, and educational level. Healthy controls are tested at baseline, and 3
and 12 months after this baseline assessment.

Conducting neuropsychological research provides no risk for participants.
The measurement take only some time (prospective clinical path: filling out a
few additional questionnaires; predict sub-study: maximal 1 times about 60
minutes at 24 months after surgery;

[HGG sub-study: maximal 7 times about 60 minutes at 6, 9, 12, 15, 18, 21 , 24
months after surgery) and some mental effort for patients and control subjects.
There is no physical load.

APOE-substudy: Blood samples containing DNA material for APOE genotyping have
already been obtained as part of routine clinical care, and stored
anonymously-coded for *further use* at the laboratory for Clinical Pathology
Midden Brabant (ETZ) only if patients made no objection, and will be
transferred in that way to the clinical chemical and hematology lab.
Neuropsychological data have already been collected in the other substudies of
the current protocol. Therefore, there is no additional effort or burden for
patients (of whom, since the start of the study in 2010, an estimated number of
170-200 patients will have been deceased, and another substantial but unknown
number will be transferred for treatment to other hospitals) associated with
APOE genotyping. Patient*s privacy and identity will be protected by careful
and responsible handling and storage of the anonymously-coded material and data
(see protocol).]