Summary

The research described in the present
thesis focuses on frequent problems in
dementia which all put a high burden on
the quality of life of both, the demented
patients themselves and their caregivers.
These problems not only consist of cognitive
disabilities, but also of disturbances in
behaviour, mood and the circadian regulation
of sleep, hormones and temperature.
The general hypothesis studied in this
thesis is that deterioration of the suprachiasmatic
nucleus (SCN) is for a large part
responsible for disturbed functionality of
the circadian timing system (CTS), and
contributes to disturbances in sleep, mood,
behaviour and cognition in demented
elderly. Moreover, we hypothesize that
reactivation of the biological clock by the
proper stimuli will improve the functionality
of the biological clock, or prevent its
deterioration. According to this hypothesis,
enhanced exposure to the stimuli to which
the biological clock is most sensitive, i.e.
bright light and melatonin, should be a
rational method to ameliorate sleep disturbances
and to improve mood, behavioural
and cognitive disturbances, at least as far as
they are under the influence of the CTS.
Chapter 2 reviews how age-related
degeneration in the core of the CTS, the
suprachiasmatic nucleus, and the resulting
weak or altered output of the system,
have negative implications for health, sleep,
mood, cognitive performance and overall
well-being of healthy and demented elderly.
Given these negative consequences, it is of
importance to investigate which mechanisms
underlie the degeneration of the
CTS in order to be able to develop rational
treatment strategies. We demonstrate how
aging can be paralleled by a diminishing
input of environmental light to the CTS.
This condition of chronically decreased
activation could contribute to neuronal
shrinkage and consequently a poor expression
of rhythms, paraphrased as ‘use it or
lose it’. We review the studies that generally
confirm that bright light contributes
to the expression of rhythms in core body
temperature, melatonin and sleep-wakefulness
in healthy and demented elderly.
Chapter 3 reviews age-related changes
in the major internal stimulus to the
CTS, the pineal hormone melatonin. The
circadian rhythm in melatonin production
is, in a feedback system, regulated
by the SCN itself, resulting in low daytime
circulating levels of melatonin and
an increase of circulating melatonin after
darkness onset. The relation between the
age-related changes in melatonin levels
and sleep is discussed in this chapter.
Based on the hypothesis that there is a
relationship between the increased prevalence
of sleep-disturbances and decreased
night-time melatonin levels in elderly,
several studies have been performed to investigate
the effect of exogenous melatonin
supplementation on sleep in elderly and
demented subjects. An overview of these
findings is presented and the various results
are discussed. We concluded that there is the
need for larger studies before widespread
use of melatonin in sleep disorders can be
advocated. These studies should have the statistical
power to elucidate which subgroups
of patients can be expected to show a positive
effect of melatonin and which cannot.
Chapter 4 focuses on the functional
neurobiology of the central pacemaker
in major depression, an other condition
in which the CTS is disturbed. Data of a
post-mortem study are presented, comparing
vasopressin (AVP) immunoreactivity
and AVP m-RNA in the SCN between
depressed and non-depressed subjects.
We found that in depressed subjects, the
number of AVP-IR neurons in the SCN was
more than one and one-half times higher
than in controls, while the total masked
area of silver grains, as an estimate of the
amount of AVP-mRNA, was about one
half that of controls. These findings suggest
that in depressed patients the transport
of AVP is even more reduced than
177 Summary
its synthesis in the SCN, resulting in an
impaired functional ability of the CTS.
Chapter 5 presents a study investigating
the relation of two types of measurement
of sleep disturbances; i.e. actigraphy and a
questionnaire, the Circadian Sleep Inventory
for Normal and Pathological States
(CSINAPS). We found good correlations
between the questionnaire items about
habitual timing of sleep and wakefulness
and their actigraphic counterparts. However,
caregivers overestimated the actual
time between sleep onset and offset by
more than 1.5 hours. The assessment of
sleep and wake disturbances in demented
elderly by the CSINAPS can be best performed
by the parallel use of actigraphy.
Though, if sleep-disordered breathing
and leg movements are a focus of interest,
additional assessments are needed.
Chapter 6 describes the association
between actigraphic estimates of the
sleep-wake rhythm and a range of functional
domains that contribute to wellbeing
in demented elderly patients.
Cognitive, functional, behavioural and
emotional states showed moderately strong
correlations with multiple rhythm variables.
Partial correlations indicated that this
could not only be attributed to a uniform
worsening with advancing cognitive decline.
Stepwise regressions indicated three
most distinctive rhythm variables: (1) the
interdaily stability of the 24-hour rhythm
was most strongly, negatively, related to
cognitive decline and depression; (2) the
median level of daytime activity was most
strongly, negatively, related to impairments
of function, of activities of daily living, and
of social interaction; (3) nocturnal restlessness
was secondarily, positively, related to
impairments of function and of social interaction.
This raises the possibility that treatments
that enhance daytime activity and
the stability of the rest-activity rhythm may
improve these components of well-being.
Chapter 7 presents the results of longterm
(up to 3.5 years) daily supplementation
of the circadian synchronisers light
(± 1000 lux) and/or melatonin (2.5 mg)
on cognition and actigraphic estimates of
sleep-wake rhythms of 189 mostly demented
elderly residents of group facilities in 12
nursing homes. This first study on longterm
stimulation of the human CTS showed
that prolonged administration of combined
melatonin and whole-day bright light treatment
in mostly demented elderly residents
of group facilities, induces effects that in
combination can be regarded as clinically
relevant. A further important finding is that
the improvement of the sleep-wake rhythm
contributed to attenuation of cognitive
decline, with an effect size comparable to
the effect that acetylcholinesterase inhibitors
have been reported to bring about in
a younger, less affected and more homogeneous
group of Alzheimer patients.
Chapter 8 reports on the non-cognitive
outcomes of long-term application
of bright light and/or melatonin
in mostly demented elderly residents of
group facilities. Light ameliorated depressive
symptoms by 19% and limitations of
activities of daily living by 11%. Melatonin
ameliorated the severity and distress of
psychiatric symptoms in subjects about
to drop out of the study due to nursing
home placement or death by 26% per year
and 45% per year respectively. However,
melatonin adversely influenced the ratings
for positive and negative observed
affect, and for withdrawn behaviour. These
adverse effects were partly counteracted if
melatonin was given in combination with
light. The combined treatment furthermore
attenuated aggressive behaviour by 9%.
Chapter 9 discusses the findings of
the studies described in the thesis and
the answered and unanswered research
questions. The primary question of the
present thesis was whether chronic
treatment with light and/or melatonin
178 Summary
remains effective in the long term.
We can finally conclude that this is the
case and that most effects even increase with
the duration of treatment. These findings
strongly suggest that continued stimulation
of the biological clock of demented elderly
is needed to keep it ticking loud enough to
be heard by the brain systems involved in
the regulation of sleep, mood and cognition.
Future research should address the question
whether a lower dose of melatonin
would be as effective on the long-term, but
without the adverse effect on mood found
with a daily dose of 2.5 mg. For the time being,
however, the best long-term effect can
be obtained with the combination of 1000
lux light and 2.5 mg melatonin per day.