Continuous CSF and plasma sampling method for amyloid biological variability in healthy volunteers and patients with Alzheimer*s disease.

Alzheimer*s disease (AD) is a neurodegenerative disorder characterized by the
accumulation of extracellular senile plaques and intracellular neurofibrillary
tangles (NFTs) in cortical and limbic brain regions. Until now, during life
only a "probable AD* diagnosis is possible, as based on clinical features and
the results of neurological and neuropsychological testing. An accurate and
early diagnosis is essential for appropriate support and treatment of dementia
patients, since drugs for the symptomatic treatment of AD are currently
available and drugs that may slow or halt the progression of the disease are
being developed.
Given the favorable diagnostic accuracy to define or exclude the diagnosis AD
amongst patients with dementia, CSF analysis of Aβ42, t-tau and p-tau proteins
has obtained a position of growing importance in dementia diagnostics. Although
much attention has been paid to pre-analytical (e.g. sampling and storage
conditions) and analytical requirements (e.g. test characteristics), until
recently little was known about fluctuations in concentrations of these
biomarkers over time. Several studies showed that long-term fluctuations were
minor, but recent studies in which CSF was collected hourly over a 36-hours
period, demonstrated that diurnal fluctuations may considerably affect Aβ
concentrations, with variations in the concentrations over 36 hours of at least
a factor 2-3 . These studies suggested that the specific timing of CSF sampling
is important in establishing Aβ concentrations. Further elaboration of these
diurnal variation is a necessary precondition to be able to implement the CSF
measurements in clinical practice in memory clinics. Diurnal fluctuations have
not been proven in Alzheimer patients, but if these are similar or larger,
strict protocols should be used for CSF collection in order not to jeopardize
valid interpretation of these tests. This clarifies the direct clinical
relevance of this study: if the variability is too high the current clinical
practice should absolutely change.

To explore diurnal fluctuation in CSF Aβ40, Aβ42, sAPPβ, t-tau and phospho-tau
concentrations over 36 hours as well as cerebral production and clearance
rates in healthy elderly volunteers and patients with mild stage of Alzheimer*s
disease. Furthermore, Aβ40 and Aβ42 plasma concentrations will be measured.

This study is a feasibility and reliability study to explore the cerebral
specific proteins Aβ40, Aβ42, sAPPβ, t-tau and phospho-tau in CSF and Aβ40,
Aβ42 in plasma. This study will be performed in the UMC St Radboud at the
Department of Geriatric Medicine. 6 healthy volunteers and 6 patients with mild
stage Alzheimer*s Disease (>= 50 years) will participate in the trial. All
patients will undergo the same procedures.

Screening
From three weeks until 2 days before study start screening will be performed.
The physician will check if the subject is eligible. Medical history, recent
and current medication use will be recorded. General physical examination will
be performed and height, weight, blood pressure, heart rate and body
temperature will be measured. Furthermore, and ECG will be recorded and blood
will be drawn. If the subject is a woman, she should be post-menopausal.

Hospitalization
When all screening results are available and the participant is eligible, the
patient will be requested to be admitted to the hospital within 3 weeks after
the screening visit. This admission will take approximately 3 days (60 hours).
The participants are admitted on day -1 at around 20:00 and will be fasting
from that time. Furthermore, blood will be drawn and an ECG will be recorded
at day -1.
The participants will receive a spinal subarachnoidcatheter, to be inserted by
anesthesiologist. Furthermore, the participants will receive an intravenous
catheter in order to draw blood.
During the following 36 hours, spinal fluid and blood will be drawn every hour.
In total approximately 216 ml of liquor and 216 ml of blood will be drawn
during this period.
Furthermore, blood pressure, heart rate and body temperature will be measured
three times a day (in the morning, at noon and in the afternoon) at day 1 and
2.
After 36 hours the spinal and intravenous catheters will be removed. The
participant will remain in the hospital for another 12 hours for observation.

Follow up visits:
An outpatient follow up visit and a follow up visit will be performed by phone
on day 7 and day 30 respectively.

Due to insertion of the spinal catheter and liquor sampling, some people
experience headache which can last for several days. Infection can occur at
injection site or deeper (meningitis). Liquor leakage at catheter insertion
site is possible. In order to minimize the risk of infection and other
complications, the spinal catheter will be inserted under the aseptic
conditions at the operation theatre by an experienced anesthesiologist (local
anesthesia is provided). After removal of the spinal catheter, the participant
will remain in the hospital for another 12 hours for observation.

Blood drawing can cause discomfort, such as pain or hematomas at the site of
venapunction. Local blood clots and infections can occur, but this is rare.
During hospitalization, during 36 hours blood and spinal fluid will be sampled
every hour. The spinal catheter in the lower back en the intravenous catheter
are inserted in such a way that the participant*s hindrance of repeated
sampling is minimal.