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Differential Circadian Rhythm Disturbances in Men with Alzheimer Disease and Frontotemporal Degeneration
David G. Harper, PhD;
Edward G. Stopa, MD;
Ann C. McKee, MD;
Andrew Satlin, MD;
Patricia C. Harlan, BS;
Rachel Goldstein, BS;
Ladislav Volicer, MD, PhD
Arch Gen Psychiatry. 2001;58:353-360.
ABSTRACT
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Background Caregiver exhaustion is a frequent consequence of sleep disturbance
and rest-activity rhythm disruption that occurs in dementia. This exhaustion
is the causal factor most frequently cited by caregivers in making the decision
to institutionalize patients with dementia. Recent studies have implicated
dysfunction of the circadian pacemaker in the etiology of these disturbances
in dementia.
Methods We studied the activity and core-body temperature rhythms in a cohort
of 38 male patients with a clinical diagnosis of probable Alzheimer disease
(AD) approximately 2 years before death. These patients were later given a
confirmed diagnosis of AD (n = 23), frontotemporal degeneration (FTD) (n =
9), or diffuse Lewy body disease (DLB) with mixed AD or FTD pathologies (n
= 6) after autopsy and neuropathological examination. Physiological rhythms
of patients with AD and FTD were then compared with a group of normal, elderly
men (n = 8) from the community.
Results Alzheimer patients showed increased nocturnal activity and a significant
phase-delay in their rhythms of core-body temperature and activity compared
with patients with FTD and controls. The activity rhythm of FTD patients was
highly fragmented and phase-advanced in comparison with controls and apparently
uncoupled from the rhythm of core-body temperature.
Conclusions Patients with AD and patients with FTD show different disturbances in
their rhythms of activity and temperature compared with each other and with
normal elderly patients.
INTRODUCTION
SLEEP DISTURBANCES are common and disruptive symptoms of disorders characterized
by dementia. The sleep-pattern disturbances seen in this population include
initial and terminal insomnia, frequent nocturnal awakenings, and sleep reversal1, 2 and exceed those found in healthy elderly
volunteers in both frequency and duration.3
Insomnia in demented patients imposes a great burden on caregivers, impedes
their ability to function normally, and is the leading cause of institutionalization
in individuals with a dementing illness.4, 5
Studies of motor behavior suggest that disruption of the sleep-wake cycle
may be caused by a decreased ability to maintain a stable pattern of diurnal
arousal and nocturnal quiescence—a pattern normally influenced by circadian
rhythmicity.6, 7, 8, 9
Circadian control of the timing of the sleep-wake cycle is mediated
by the endogenous circadian rhythm generated by the suprachiasmatic nuclei
(SCN) of the hypothalamus.10, 11, 12, 13
Core-body temperature is the most direct and measurable manifestation of this
output,14 especially under constant routine
conditions.15 Many subcortical structures,
such as the basal forebrain, dorsal and central superior raphe nuclei, and
the reticular formation of the pons and medulla, also seem to be involved
in the initiation of sleep and the oscillation between REM and non-REM states.16, 17, 18, 19, 20, 21, 22
Current thinking maintains that there is a dynamic interplay between the circadian
pacemaker in the SCN modulating arousal (process C) and flexible homeostatic
influences modulating sleep tendency (process S) possibly based in these other
subcortical structures.12, 23 All
of these structures potentially could be damaged as a consequence of Alzheimer
disease (AD)16 and frontotemporal degenerative
dementias (FTD),24 and their deterioration
could explain many sleep architecture and continuity changes seen in these
illnesses.1, 25
Alzheimer disease and FTD are both progressive, degenerative dementias
characterized by global loss of cognitive ability and accompanied by a wide
range of noncognitive symptoms. Frontotemporal degenerative dementias often
present initially with progressive aphasia and personality changes, while,
in the initial stages of the illness, memory remains intact. In AD, memory
loss is often the first symptom reported and personality remains intact for
a longer duration. As the illnesses progress, symptom presentations become
more similar between these 2 forms of dementia, and a recent study found that
the specificity of the diagnosis of probable AD, using the best criteria available,26 was 0.23.27 Therefore,
these 2 dementias become virtually indistinguishable from each other without
pathological examination. Such examination reveals either the presence of
amyloid plaques sufficient for the diagnosis of AD or the neuronal loss of
the frontal and temporal regions, without plaque formation, which is indicative
of FTD.
There are several lines of evidence supporting the hypothesis that changes
in the endogenous circadian system caused by a dementing illness28
lead to the disruption of the rest-activity and sleep-wake rhythms. Our group
has shown that there is a phase-delay in the circadian rhythm of temperature
and activity in patients with probable AD and a reduced synchronization between
rhythms of temperature and activity.8 Patients
with dementia also show specific patterns of destruction in the SCN, which
could result in a disruption of these circadian rhythms.29, 30
Finally, light treatment, which is effective in changing the circadian rhythm,14 may be effective in treating sleep-wake disturbances
in these patients.7, 31, 32, 33
The current work improves on these earlier studies by examining antemortem
activity and temperature data in the light of postmortem diagnosis made approximately
2 years later.
There are at least 2 possible explanations for the putative chronobiologically
based sleep and rest-activity rhythm disturbances in patients with dementia.
The first hypothesis is that the institutions in which these patients were
studied caused the chronobiological disturbance by providing insufficient
signals or zeitgebers to entrain (coordinate temporally
with the environment) the patient's circadian rhythms. Low light levels during
the day and increased nocturnal lighting, endemic to these institutions,32 and also found in the home environment,34
may make it difficult to achieve robust entrainment to the environment. With
this "environmental" hypothesis, no dysfunction of the circadian system is
necessary to explain the rest-activity and sleep-wake disturbance seen in
patients with dementia. The second hypothesis is that the circadian system
in these patients is selectively impaired, and, as a result, they are unable
to maintain entrainment. If the first hypothesis is true, there should be
no difference between the different diagnostic categories, and impairments
to the circadian rhythm should be similar across all patients. If the differences
are caused by central changes related to the disease process, then differences
may emerge between the diagnostic groupings. Understanding the origin of these
circadian changes then may have diagnostic utility and indicate proper treatment
strategies.
SUBJECTS AND METHODS
SUBJECTS
Thirty-eight men with dementia with a mean ± SE age of 70.2 ±
1.0 years, an age of onset of 60.7 ± 1.1 years, and a duration of illness
at the time of recording of 11.8 ± 0.7 years were sampled from a clinical
population at the EN Rogers Memorial Veterans Hospital, Bedford, Mass. All
subjects were evaluated by a board-certified psychiatrist (L.V.) on enrollment
and met National Institute of Neurological and Communicative Disorders and
Stroke and the Alzheimer's Disease and Related Disorders Associations criteria
for probable AD.26 They had no lifetime history
of major affective illness, schizophrenia, or substance abuse, except for
4 subjects who had some background of alcohol abuse yet met criteria for probable
AD. All dementia subjects at the time of physiological recording were severely
impaired, ambulatory and nonambulatory, Reisberg stage 5 to 635
patients. They required 24-hour institutional care, were free from significant
intercurrent illnesses, and were taking no antipyretic medication for at least
24 hours before the physiological recordings. The comparison subjects for
the physiological recordings were 8 elderly male volunteers from the community
recruited through the Harvard Project on Aging and the Massachusetts Institute
of Technology's Clinical Research Center. They had a mean ± SE age
of 72.8 ± 2.1 years and no evidence of dementia, as verified by Mini-Mental
State Examination and clinical evaluation by a board-certified psychiatrist
(A.S.). They otherwise met all the same criteria for inclusion as the dementia
subjects. Controls were studied at the Massachusetts Institute of Technology's
Clinical Research Center, which closely simulates a hospital environment.
They were admitted to the unit the day the study began.
PROCEDURES
Circadian Studies
After institutional review of the project and the receipt of informed
consent from the control subjects and the next-of-kin of the dementia subjects,
physiological rhythms were studied for 72 hours, beginning at noon on the
first study day, using ambulatory monitors. The unit schedule for patients
and controls was lights out at 10 PM and lights on at 6 AM. Controls were
allowed free mobility, including outside the unit during the study. Patients
were allowed the same privileges as controls as far as possible within the
constraints of their illness. Motor activity was recorded using an AM-16 activity
monitor (AMI, Ardsley, NY), worn on the nondominant ankle and sensitive to
accelerations of 0.1g (1 activity count) by the mechanical
action of a piezoelectric bender and counterweight. Activity counts were accumulated
in 5-minute epochs, and the resultant quantity was then written to memory.
Temperature was measured by a temperature sensitive thermistor (Series 400;
YSI Inc, Yellow Springs, Ohio), accurate to 0.1°C and placed in the rectum
to a depth of 10 cm. This probe was connected to an ambulatory temperature
monitor (Mini-Logger; Mini-Mitter Corp, Sun River, Ore), which sampled the
temperature every 6 minutes and wrote it to memory for later retrieval. All
nursing care and other patient interventions were noted for later editing
of data artifacts, and all temperature and activity records were at least
80% complete.
Diagnosis at Autopsy
Physiological data were recorded 1.74 ± 0.21 (mean ± SD)
years before death and autopsy. All brains were subjected to a standardized
neuropathologic examination. Brains were fixed for at least 4 weeks in 10%
neutral buffered formalin to standardize shrinkage during fixation. Fourteen
brain areas were routinely sampled based on their suitability for diagnosing
AD, FTD, and dementia with Lewy bodies (DLB). The diagnosis of AD was guided
by the consensus criteria established by the Consortium to Establish a Registry
for Alzheimer's Disease36 and by the work of
Braak and Braak,37 both endorsed by the International
Working Group from the National Institute on Aging and the Reagan Institute.38 Diagnosis of DLB or Parkinson disease was made using
criteria established by the Dementia With Lewy Bodies International Workshop.39 Significant vascular disease, a diagnosis of exclusion,
was based on the criteria outlined in the National Institute of Neurological
Disorders and Stroke–Association Internationale pour la Recherche et
l'Enseignement en Neurosciences International workshop.40
The diagnosis FTD refers to non-Alzheimer degenerative disorders that primarily
affect the frontal and temporal lobes. This category includes cases that fit
the classic description of Pick disease with severe cortical atrophy, neuronal
loss, gliosis, Pick bodies, and ballooned neurons, as well as cases of frontal
and/or temporal atrophy, with or without ballooned neurons, without Pick bodies.
This classification scheme also includes most cases of corticobasal ganglionic
degeneration, frontotemporal dementia, non-Alzheimer frontal lobe dementia,
chromosome 17–linked dementia, and progressive subcortical gliosis.
DATA ANALYSIS
Representative recordings of activity and temperature in the 3 diagnostic
groupings are shown in Figure 1.
Motor activity was assessed for mean diurnal (6 AM to midnight) and nocturnal
(midnight to 6 AM) activity (activity counts per 5-minute epoch). Gross motor
activity was also assessed using the M10 and L5 indices.6
The M10 is the mean activity counts per hour of the 10 most active hours in
the 24-hour period. The L5 is the mean activity counts per hour of the 5 least
active hours in the 24-hour period.
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Figure 1. Representative samples of activity
recorded in 5-minute epochs and core-body temperature data recorded in 6-minute
epochs of 3 subjects in this study. A, Representative data from a normal elderly
subject. B, Representative data from a subject with Alzheimer disease. C,
Representative data from a subject with frontotemporal degeneration.
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Interdaily stability, a periodogram-based algorithm measuring day-to-day
stability of the rhythm, and intradaily variability, a measurement of the
fragmentation of the activity rhythm that assesses the period-to-period variability
of the rhythm, were used as nonparametric measures of the circadian rhythm
of motor activity.6 These methods of activity
analysis make no assumptions about the shape of the data or the continuity
of the function, and therefore may be more sensitive than cosinor and other
parametric methods.32
Cosinor analysis was used to model a circadian rhythm to the temperature
and activity data.41 Cosinor analysis makes
a mathematical model of the data by estimating the mesor (the point around
which the model oscillates), amplitude (the distance from the mesor to the
peak), and phase (the time of the model peak) of the circadian rhythm, and
calculates a goodness-of-fit (the square of the least squares correlation
[R2]) of the model to the data. For these
analyses, we fixed the frequency at 1 cycle per day and performed a 2 harmonic
fit (1 and 2 cycles per day) to the activity and temperature data. To control
for differing overall activity levels between subjects, we measured amplitude
of the activity rhythm as relative amplitude (amplitude per mesor).
Three groups (control, AD, and FTD) were directly compared in this study
using a between-subjects analysis of variance with Tukey post hoc comparisons.
The significance level for all tests was set at  = .05 (2-tailed).
In addition, dementia patients were also tested for systematic differences
between the different diagnoses in age, age of onset of illness, duration
of illness, and length of hospitalization. All values are reported as mean
± SE except where noted. Patients who did not evidence a circadian
rhythm of activity or temperature were also excluded from further analysis
if an F test comparison of the cosinor fit to a mesor fit had a value P>.05.41
RESULTS
DIAGNOSTIC COMPOSITION OF THE SAMPLE
Thirty-eight subjects underwent postmortem, neuropathological examination;
27 were given a primary diagnosis of AD, and 4 were diagnosed with both AD
and DLB. One of these 4 was also diagnosed as having multi-infarction dementia.
Ten patients were diagnosed as having FTD and 1 patient was diagnosed as having
DLB. Of the 10 patients diagnosed as having FTD, 5 patients were given a diagnosis
of Pick disease and 5 patients were given a diagnosis of corticobasal ganglionic
degeneration. One of the patients with FTD (Pick) was diagnosed as having
DLB, as well. Because of the parkinsonian motoric features of DLB affecting
the circadian analysis, the small number of subjects given this diagnosis,
and the problems of mixed diagnosis inherent with this group, we excluded
them from further study. This left 23 patients with AD, 9 patients with FTD,
and 8 normal elderly subjects for analysis. There were no differences between
the ages of the control (72.8 ± 2.1), AD (70.6 ± 1.2), and FTD
(69.4 ± 1.8) groups (F2,37 = 0.45, P
= .60). The age of dementia onset of the AD (59.9 ± 1.3) and FTD (62.2
± 2.0) groups were similar (F1,30 = 0.87, P = .40), although mean ± SD duration of illness was longer
in AD (13.0 ± 0.7) than in the FTD (9.3 ± 1.1) group (F1,30 = 8.42, P = .007).
ACTIVITY LEVELS
There were several differences in the gross activity levels of the different
diagnostic groups (Figure 2A).
Mean diurnal activity was significantly higher in AD patients than in FTD
patients, although both were significantly lower than control levels (F2,35 = 11.38, P<.001). Nocturnal activity
levels were significantly higher in AD patients than in controls. The M10
and L5 results confirm the impressions from the diurnal and nocturnal activity
analyses (Figure 2B). The M10 levels
were significantly reduced in both dementia groups (F2,35 = 9.39, P<.001), with FTD patients having lower levels than
AD patients. The L5 was significantly elevated in the AD group over both FTD
and controls (F2,35 = 4.760, P = .01).
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Figure 2. Locomotor activity (mean ±
SE) in subjects with Alzheimer disease (n = 23), frontotemporal degeneration
(n = 9), and controls (n = 8). A, Diurnal and nocturnal activity. Diurnal
activity is defined as activity occurring from 6 AM to midnight. Nocturnal
activity is defined as activity occurring from midnight to 6 AM. B, The M10
and L5 levels. The M10 is defined as the 10 most active hours during the day,
and the L5 is defined as the locomotor activity occurring during the 5 least
active hours during the day. Both measurements are independent of time of
day.
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Interdaily stability was lower in both diagnostic groupings than in
controls (F2,35 = 6.13, P = .005), and
there were no differences between the 2 diagnostic groups (Figure 3A). Intradaily variability (Figure 3B), however, was higher in the FTD group than in both controls
and AD (F2,35 = 5.39, P = .009).
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Figure 3. Nonparametric measurements of
circadian rhythm of activity in subjects with Alzheimer disease (AD) (n =
23), frontotemporal degeneration (FTD) (n = 9), and controls (n = 8) (corticobasal
ganglionic degeneration [CBD]). A, Scatterplot of interdaily stability, a
measurement of the strength of the circadian rhythm. Tukey test of AD compared
with controls, P = .02; FTD compared with controls, P
= .03; and AD compared with FTD, P = .94. B, Scatterplot of intradaily
variability, a measurement of the fragmentation of the rest-activity rhythm.
Tukey test of AD compared with controls, P = .99; FTD compared
with controls, P = .04; and AD compared with FTD, P
= .01.
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COSINOR ANALYSES OF ACTIVITY AND TEMPERATURE RHYTHMS
Several patients showed no significant improvement in the measured goodness-of-fit
of a 1 cycle per day rhythm of activity or temperature when compared with
a mesor fit alone indicating that the data lacked circadian rhythmicity. One
AD patient lacked a temperature rhythm, and 3 patients with AD had no significant
activity rhythm. All FTD patients had significant temperature rhythms, although
1 FTD patient had no significant activity rhythm. The lack of circadian rhythm
in activity or temperature was not specific to diagnosis (P>.05, by Fisher exact test). Activity or temperature data lacking
a demonstrable circadian rhythm were excluded from further cosinor analysis,
leaving the temperature rhythms of 22 AD subjects to compare with 9 FTD subjects
and 8 controls. Activity rhythms of 20 AD subjects were compared with 8 FTD
patients and 8 controls.
The mesor of the activity rhythm was lower in both dementia diagnoses
than in the control group, as would be expected from the results of the measurements
of gross motor activity (Table 1). The mesor in FTD patients was lower than the mesor in AD patients. Relative
amplitude was similar in the 3 groups. However, the phase time (Figure 4A) was significantly delayed in AD and advanced in the FTD
group when compared with the normal elderly group. Correlation of the data
to the model was lower in the FTD group when compared with both control and
AD groups (Table 1).
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Table 1. Cosinor Analysis of the Activity Rhythm in Subjects With Alzheimer
Disease (AD), Subjects With Frontotemporal Degeneration (FTD), and Controls
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Figure 4. A, Acrophase of the rhythm of
activity as measured by cosinor analysis in Alzheimer disease (AD) (n = 20),
frontotemporal degeneration (FTD) (n = 8), and controls (n = 8). Tukey test
of AD compared with controls, P = .03; FTD compared with controls, P = .04; and AD compared with FTD, P = .0001. B, Acrophase
of the rhythm of core-body temperature in subjects with AD (n = 22), FTD (n
= 9), and controls (n = 8). Tukey test of AD compared with controls, P = .003; FTD compared with controls, P = .69; and AD
compared with FTD, P = .04. CBD indicates corticobasal ganglionic
degeneration.
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Cosinor analysis revealed that the mesor and amplitude of the circadian
rhythm of temperature, along with the goodness-of-fit of the data to the model,
were similar in the 3-group model (Table
2). The phase of the temperature rhythm (Figure 4B) was significantly delayed in the AD patients but not
in the FTD patients.
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Table 2. Cosinor Analysis of the Temperature Rhythm in Subjects With
Alzheimer Disease (AD), Subjects With Frontotemporal Degeneration (FTD), and
Controls
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COMMENT
Several important differences emerge in the structure of activity and
temperature rhythms in progressive, degenerative dementia when diagnosis is
taken into account. Nocturnal activity is higher in AD when compared with
normal elderly controls, an effect not seen in FTD. Fragmentation of the activity
rhythm occurs in FTD, but not AD, as evidenced by increased intradaily variability
and lowered circadian goodness-of-fit when compared with a normal elderly
comparison group. The circadian rhythm of temperature is phase-delayed (the
time of peak temperature is later) in AD, with a commensurate delay in the
activity rhythm compared with normal elderly individuals. In FTD, the temperature
phase is normal and the activity phase is advanced (time of peak activity
is earlier). These results confirm the findings of previous studies,42, 43 in which disturbances in the expression
of a normal rhythm of activity and a disturbance of the sleep-wake rhythm25, 44 are apparent in patients with AD
and FTD.
The nocturnal activity increase seen in AD in this study could be accounted
for in 2 ways. The first explanation is that the phase-delay of the activity
rhythm in AD causes actual diurnal-type activity to be phase-shifted into
the defined nocturnal period. The second explanation is that the increase
could be caused by an inability of AD patients to achieve normal nocturnal
quiescence. The increase in the L5 in AD demonstrates that this increase in
nocturnal activity cannot be entirely explained by delayed activity phase.
The L5, which quantifies activity occurring during the 5 least active hours
of the day, whenever they occur,6 shows a similar
pattern of increase in AD as in the nocturnal activity measurement. Therefore,
AD patients show a remarkable inability to achieve normal periods of quiescence
at any time during the diurnal-nocturnal cycle.
The rhythm of oscillation in core-body temperature is often taken as
a marker of the activity of the SCN and of the endogenous circadian pacemaker.14 Measurements of phase of the circadian rhythm of
core-body temperature provide information about the state of internal timekeeping
relative to the environment. While our patients were not studied under true
constant routine conditions in this investigation,45
the recorded temperature rhythm may provide an approximation of the endogenous
circadian phase in these subjects. Sleep-wake and rest-activity rhythms are
influenced and often determined by the phase of the circadian pacemaker.11, 13 Therefore, the observed phase-delay
in the rhythm of core-body temperature could be indicative of a phase-delay
in output of the SCN, which is then causing the phase-delay observed in the
rest-activity rhythm of our subjects with AD.
It is also possible that phase-delay in the rest-activity rhythm, perhaps
caused by weakening of the sleep homeostat,23
is causing phase-delay in the temperature rhythm. In this scenario, the observed
core-body temperature rhythm's phase-delay is caused by additional evening
and night light exposure. This additional stimulus affects the phase-delay
portion of the phase-response curve to light.46
This explanation is unlikely, however, since FTD patients, who have a phase-advanced
activity rhythm, do not show a commensurate phase-advance in their temperature
rhythm. The temperature rhythm of FTD patients is remarkable for its similarity
to normal elderly, even with activity rhythms that are more disturbed than
those seen in AD. Another possibility is that afternoon agitation, often observed
in AD patients, could be influencing the activity and consequently the temperature
rhythm. Further studies, with more control of activity, could help to elucidate
the mechanism of the phase-delay seen in AD.
Frontotemporal degeneration patients, therefore, show a fundamentally
different type of circadian abnormality than do AD patients. The expression
of an entrained circadian rhythm, as an organized pattern of rest-activity,
is compromised in FTD, even while a normal rhythm of core-body temperature
is maintained, while, in AD, both central pacemaker and behavioral expression
are altered. Therefore, in AD, treatments that act at the level of the central
pacemaker, such as light or melatonin, may be effective in treating the behavioral
disturbances. Dementia patients have been noted to have abnormalities in their
rhythms of melatonin secretion.47, 48
This dysfunction has been noted not only in patients with clinical diagnosis
of AD,9 but confirmed after postmortem analysis.49 Light therapy, given after the temperature nadir,
may also be an appropriate treatment. However, determining the precise temperature
nadir before beginning any chronobiological treatment is important since it
can occur very late in some subjects, sometimes later than 11 AM. If light
were given before or during the time of the temperature nadir, the phase could
be shifted in the direction opposite from expectation. Chronobiological treatments,
aimed at the SCN and the endogenous circadian rhythm in FTD, are unlikely
to be effective in treating the disrupted rest-activity rhythms of this form
of dementia. In FTD, the central pacemaker seems to be functioning normally,
with difficulties emerging downstream from the SCN. Further work is needed
to understand the nature of the rest-activity rhythm disturbance in FTD.
One important limitation of this investigation is that only male dementia
patients were studied. Women show different patterns of sleep and circadian
physiology during aging than men.50, 51, 52, 53
Therefore, the present results should be interpreted cautiously regarding
their generalizability to women. Another clear limitation is the advanced
state of dementia in these subjects. Sleep disturbance can occur early during
the course of a dementing illness.4, 54
Further work could clarify the contributing roles of the circadian timing
system and the sleep homeostat in early dementia.55
These patients also were studied without the benefit of a constant routine.56 A constant routine protocol would allow for more
precise quantification of endogenous circadian phase and amplitude of core-body
temperature. The placement of the activity monitor on the ankle could also
lead to our activity measurements being confounded by the presence of periodic
leg movements of sleep, tremor, or akathisia in some of our subjects.
This study does support the hypothesis that central changes cause the
observed, rhythmical changes identified previously in AD and FTD. In addition,
testing circadian disturbances may be an effective way to differentially diagnose
these 2 degenerative dementias. Localizing the exact nature of disturbance
could lead to new treatments for these debilitating symptoms of dementia.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
Supported by grants AG09301 (Drs Satlin and Volicer) and AG13846 (Dr
Volicer) from the National Institute on Aging, Bethesda, Md, and the Department
of Veterans Affairs, Washington, DC.
Presented in part at the Society for Neuroscience Annual Meeting, Miami,
Fla, October 25, 1999, and the World Alzheimer Congress, Washington, DC, July
11, 2000.
We thank Jennifer Clarke Byington for excellent editorial assistance.
From the Department of Psychiatry, Harvard Medical School,
Boston, Mass (Drs Harper and
Satlin); McLean Hospital, Belmont, Mass (Drs Harper, Satlin, and
Volicer and Mss Harlan and Goldstein); the Department of
Psychology, Tufts University, Medford, Mass (Dr Harper); the
Department of Pathology, Brown University, Providence, RI (Dr
Stopa); and the EN Rogers Memorial Veterans Hospital, Bedford, and
Boston University School of Medicine (Drs McKee and
Volicer).
Corresponding author: David G. Harper, PhD, Admissions Building,
McLean Hospital, 115 Mill St, Belmont, MA 02478 (e-mail: dharper{at}mclean.harvard.edu).
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