Losing sleep over Alzheimer*s disease?
Effects of sleep deprivation on cerebrospinal fluid amyloid-beta dynamics

Alzheimer*s disease (AD) is a progressive neurodegenerative brain disease
causing Alzheimer type dementia, the most common form of dementia. At present,
230,000 people in the Netherlands have AD and this number will rise to over
half a million by the year 2050. Existing therapies are, at best, symptomatic
and do not prevent the progression of the disease. In order to develop more
efficient, disease specific therapies and initiate treatment early on in the
disease, the identification of factors contributing to the development of AD
remains a very important goal.
AD is characterized by an increased production and decreased clearance of the
amyloid-beta protein (Aβ) in the brain, forming plaques, and the formation of
neurofibrillary tangles consisting of insoluble tau proteins. The cause of
these neurodegenerative processes remains unclear and although multiple
relating factors have been identified so far none can serve as effective
biomarker for early detection or treatment.
One factor that seems to hold a relation to AD is sleep. For one, AD has proven
to be associated with disruption of the sleep-wake cycle. In dementia patients
partial restoration of a disturbed sleep-wake cycle, using both light therapy
and melatonin, reduces cognitive decline. In recent animal studies a
correlation between sleep-wake cycles and Aβ deposition has been established.
Extended wakefulness was associated with increased production and subsequent
deposition of Aβ. Sleep, in contrast, led to a marked fall in Aβ production.
These findings indicate that sleep disturbance may in fact be one of the
factors triggering overproduction and deposition of Aβ. If a similar relation
between sleep disturbance and CSF Aβ levels can be demonstrated in humans, this
may point out sleepdisorders as another risk factor profiling those at risk for
AD.
A previous study performed at our department showed us that CSF AD biomarker
levels can be measured regularly over a period of 36 hours using a spinal
catheter. Here we will use this experience to measure CSF Aβ levels in relation
to sleep deprivation.

The primary objective is to determine an effect of sleep deprivation on CSF
Aβ42 levels in humans.

Secondary objectives:
-Effect of unrestricted sleep on CSF Aβ42 levels.
-Effects of unrestricted sleep and sleep deprivation on other known AD
biomarkers; Aβ40, t-tau and p-tau.
-Relation between the sleep regulatory peptide hypocretin and Aβ levels. In
animal studies inhibition of hypocretin led to increased sleep and subsequently
to reduced Aβ levels.

A randomized controlled study in 26 healthy, male volunteers, aged 40-60 yrs,
of whom 13 will undergo a night of sleep deprivation (intervention group) and
the other 13 a control night with unrestricted sleep (control group). CSF Aβ
concentrations will be measured before, during, and after the night of sleep
deprivation and before and after the control night of unrestricted sleep.
Both in the intervention group and the control group CSF A*42 concentrations
will be measured by collecting CSF with an intrathecal catheter, which will
remain in place for 20 hours.

Complications related to the placement of the intrathecal catheter are leakage
of CSF around the tube, kinking of the catheter, hematoma, CSF fistula,
superficial infection and infections of the catheter which can lead to
meningitis. These complications are rare and were not seen in our former study.
A complication of lumbar puncture that is more frequently seen is post spinal
headache. However the risk of this complication developing with lumbar puncture
is only 2.6%, according to a recent study in 1089 patients.
During a previous study at our department where during 36 hours hourly CSF
samples were drawn, post spinal headache was seen in 8 out of 12 subjects. The
intensity of the headaches varied but all were manageable with posture advice
and painkillers. This complication was probably a results of the amount of CSF
that was drawn, 216 ml over 36 hrs. Therefore, in the present study, in the
control group there will be 6 moments of CSF sampling, with a total amount of
36 ml CSF drawn. In the intervention group there will be 10 moments of CSF
sampling, with 60 ml of CSF drawn.
Sleep deprivation will lead to tiredness.