Control of Sleep and Wakefulness in Health and Disease - Progress in Molecular Biology and Translational Science - page 143

results. 30 It is possible, however, that the loss of cholinergic tone that accom-
panies AD is directly responsible for the observed loss of temporal organi-
zation of sleep and wake. In healthy older individuals without AD, there
is an increased likelihood of napping 31 and an increased rate of nocturnal
awakenings. 32 The reduction in cholinergic tone in individuals with AD
could further increase the likelihood of daytime sleep, which would reduce
the pressure for sleep to occur at night. The increased wake at night would
then lead to increased sleep during the day and so on. Given the role of sleep
in memory consolidation, this type of sleep disruption has also been hypoth-
esized to compound AD-associated dementia. 33 Amelioration of sleep dis-
ruption, therefore, could be a target to improve memory in individuals with
AD, especially early in the course of the disease.
2. THE HYPOTHALAMUS
Although the hypothalamus was identified as a key contributor to the
modulation of sleep and wake nearly a century ago by pioneering work of
Von Economo, 34 hypothalamic mechanisms went largely understudied
until the 1980s. Hypothalamic mechanisms can be grossly separated into five
groups of neurons—the hypocretin-expressing neurons of the lateral hypo-
thalamus, the suprachiasmatic nucleus (SCN, location of the circadian pace-
maker), histamine-expressing neurons, the ventrolateral preoptic nucleus
(VLPO), and temperature-sensitive neurons in the anterior hypothalamus.
Hypocretin (also known as orexin) is a neuropeptide expressed in a dis-
creet group of hypothalamic neurons. The loss of these neurons results in the
sleep disorder narcolepsy (see earlier). 35 There is strong evidence to suggest
that narcolepsy is an autoimmune-mediated destruction of hypocretin-
expressing neurons. 36 The onset of this autoimmune attack may be a con-
fluence of genetic background, age, and an appropriately timed infection.
Antistreptococcal antibodies have been found in the serum of individuals
with a recent onset of narcolepsy, implying that a recent infection by strep-
tococcus bacteria might have the capacity to trigger narcolepsy. 37 More
recently, it has been reported that there was a substantial increase in new
cases of narcolepsy following H1N1 influenza infection and after receiving
the adjuvant-coupled version of the H1N1 vaccine. 38 Whether the H1N1
virus or vaccine directly induces the autoimmune attack on hypocretin-
expressing neurons or whether they create a permissive environment
(e.g., upregulated immune activity, leakiness of the blood-brain barrier) is
not known.