Article revie...2010/07/29 · 1 牧本研究室抄読会 2010-7-29 担当：Catheline Article...

1牧本研究室抄読会

2010-7-29担当：Catheline

Article review:

Differential Circadian Rhythm Disturbances in Men with Alzheimer Disease andFrontotemporal DegenerationDavid 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

Archives of General Psychiatry 2001, 58, 353-360

Impact factor: 14.273

総評 B+

IFが 14 と非常に高い論文であった。

今回の論文は、病理解剖をして病理学的所見より確定診断をしていること、また、深部体温のリズムも

同時に測定している、という 2 点が、今までには無く、非常に貴重であった。

しかし、方法のところでは、記述に明確でないところがいくつか見られたので以下に示す。

・アクチグラフ装着率が 8 割とのことであったが、その詳細な記述が必要であった。たとえば、一人が

全く取れていないのか、各対象者が少しずつ取れていなかったのか、という点である。また、取れな

かった時間帯の記述も必要であった。もともと N 数が少ないので、特に FTD 群では、少しのデータの

欠損が結果に影響を及ぼすので、データ収集の記述は細かくすべきであった。

・ADLレベルや精神症状の記述が全く無かった。認知症の重症度も、記憶障害等の認知機能に焦点を当

てた GDS を利用しており、多くの研究で使用されており、かつ精神症状や ADLレベル等の包括的な

認知症重症度分類である CDR（Clinical Dementia Rating）を使用していなかった。

・服用中の薬剤の記述も無かった。

・Core temperature は 3 日間連続して測定しているが、肛門に 10cm のプローブを挿入して測定している

ため、その間の対象者はどうしているのかが不明であった。（例：排便等）

方法のところで、対象者の背景の記述が少ないため、考察も不明確な内容であった。

まず、FTD を病理解剖した結果、約半数が CBD であったが、それをそのまま FTD 群に入れて比較する

のは不適切であった。また、考察でよく述べられている phase-delayについては、結果であまり触れられて

いないので、解釈が出来なかった。

イギリスの研究グループによる“Disrupted sleep and circadian patterns in frontotemporal dementia”

K. N. Anderson, C. Hatfield, C. Kipps, M. Hastings and J. R. Hodges,* European Journal of

Neurology 2009, 16: 317–323”では、今回の論文とは全く逆の結果になった。この論文は対象者がコミュ

ニティーにいること、FTDの早期段階の患者が多かったが、今回の抄読論文は、入院患者で、かつ晩期の

患者を対象にしていたことも、結果が間逆になった要因として示唆されるが明らかではない。



Introduction

1. Background of the article

Insomnia in demented patients imposes a great burden on caregivers, and is the leading cause of

institutionalization in the population.

1.1 Etiology

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.

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.

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.



All of these structures potentially could be damaged as a consequence of Alzheimer disease (AD) and

frontotemporal degenerative dementias (FTD), and their deterioration could explain many sleep

architecture and continuity changes seen in these illnesses.

1.2 Pathology

As the illnesses progress, symptom presentations become more similar between AD and FTD. Therefore,

these two 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.

1.3 Relationship between endogenous circadian system and rest-activity rhythms

1.3.1 Changes in the endogenous circadian system caused by a dementing illness lead to the disruption

of the rest-activity and sleep-wake rhythms.

1.3.2 Former study of the authors 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.

1.3.3 Patients with dementia show specific patterns of destruction in the SCN, which could result in a

disruption of these circadian rhythms.

1.3.4 Light treatment, which is effective in changing the circadian rhythm, may be effective in

treating sleep-wake disturbances in these patients.



2. About hypothesis

2.1 Two main hypothesizes of the rest-activity disturbances in dementia patients.

There are at least 2 possible explanations for the putative chronobiologically based rest-activity rhythm

disturbances in patients with dementia.

2.1.1 The 1st is “environmental”hypothesis: the institutions in which these patients were studied caused

the chronobiological disturbance by providing insufficient signals or zeitgebers to entrain the patient’s

circadian rhythms. For example, low light levels during the day and increased nocturnal lighting. This

could also been found in the home environment.

2.1.2 The 2nd hypothesis is that the circadian system in these patients is selectively impaired, and, as a

result, they are unable to maintain entrainment.

2.2 Hypothesis of the article

“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. It means that the circadian system in these patients is

selectively impaired.”

Question 1:

As we all know, endogenous factors play a crucial role for the synchronization of circadian rhythms,

why author just separate external factor such as “environmental clues”alone to explain the rest-activity

disturbance? It may turn out that sleep and rest-activity disturbance of patients with dementia are caused

by environmental factors and we could resolve the problems by improve the environment. But the

institutions provide even more insufficient zeitgebers, why insomnia became one of the leading causes

of institutionalization in patients with dementia?

The authors may commit “Causal oversimplification”fallacy by claiming that “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”. This is not necessarily the case to support the

subsequent argument.

3. The purpose of the article

To test the hypothesis by examining antemortem activity and temperature data in the light of postmortem

diagnosis made approximately 2 years later.



Understanding the origin of these circadian changes then may have diagnostic utility and indicate proper

treatment strategies.

Analysis

1. Methodology of the article

1.1 Design of the study

Cohort study.

1.2 Subjects and setting

38 male with dementia was enrolled from a clinical population at the EN Rogers Memorial Veterans

Hospital.

1.2.1 Subject summary

Number Mean±S.E.SubtypeAntemortem Postmortem Ages Age of onset Duration of illness

AD 23 23 70.6±1.2 59.9±1.3 13.0±0.7*AD&DLB 4 canceledFTD 10 9 69.4±1.8 62.2±2.0 9.3±1.1

Pick disease 4CBD 5

Pick disease & DLB 1 canceledDLB 1 canceledTotal 38 32Control 8 72.8±2.11.2.2 Selection criteria

a. The diagnosis AD meets National Institute of Neurological and Communicative Disorders and

Stroke and the Alzheimer’s Disease and Related Disorders Associations criteria;

b. 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;

c. Without lifetime history of major affective illness, schizophrenia, or substance abuse;

d. Taking no antipyretic medication for at least 24 hours before the physiological recordings.

1.2.3 Patients’clinical characteristics

All dementia subjects at the time of physiological recording were severely impaired, ambulatory and

non-ambulatory, Reisberg stage 5 to 6. They required 24-hour institutional care.



Global Deterioration Scale for Assessment of Primary Degenerative Dementia (GDS)

(Also known as the Reisberg Scale)Diagnosis Stage Signs and SymptomsNoDementia

Stage 1:No CognitiveDecline

In this stage the person functions normally, has no memory loss, andis mentally healthy. People with NO dementia would be considered tobe in Stage 1.

NoDementia

Stage 2:Very MildCognitiveDecline

This stage is used to describe normal forgetfulness associated withaging; for example, forgetfulness of names and where familiar objectswere left. Symptoms are not evident to loved ones or the physician.

NoDementia

Stage 3:Mild CognitiveDecline

This stage includes increased forgetfulness, slight difficultyconcentrating, decreased work performance. People may getting lostmore often or have difficulty finding the right words. At this stage, aperson's loved ones will begin to notice a cognitive decline. Averageduration: 7 years before onset of dementia

Early-stage

Stage 4:ModerateCognitiveDecline

This stage includes difficulty concentrating, decreased memory ofrecent events, and difficulties managing finances or traveling alone tonew locations. People have trouble completing complex tasksefficiently or accurately and may be in denial about their symptoms.They may also start withdrawing from family or friends, becausesocialization becomes difficult. At this stage a physician can detectclear cognitive problems during a patient interview and exam.Average duration: 2 years

Mid-Stage

Stage 5:ModeratelySevere CognitiveDecline

People in this stage have major memory deficiencies and need someassistance to complete their daily activities (dressing, bathing,preparing meals). Memory loss is more prominent and may includemajor relevant aspects of current lives; for example, people may notremember their address or phone number and may not know the timeor day or where they are. Average duration: 1.5 years

Mid-Stage

Stage 6:Severe CognitiveDecline (MiddleDementia)

People in Stage 6 require extensive assistance to carry out dailyactivities. They start to forget names of close family members andhave little memory of recent events. Many people can remember onlysome details of earlier life. They also have difficulty counting downfrom 10 and finishing tasks. Incontinence (loss of bladder or bowelcontrol) is a problem in this stage. Personality changes, such asdelusions (believing something to be true that is not), compulsions(repeating a simple behavior, such as cleaning), or anxiety andagitation may occur. Average duration: 2.5 years

Late-Stage

Stage 7:Very SevereCognitiveDecline (LateDementia)

People in this stage have essentially no ability to speak orcommunicate. They require assistance with most activities (e.g., usingthe toilet, eating). They often lose psychomotor skills, for example,the ability to walk. Average duration: 2.5 years

(Reisberg, et al., 1982; DeLeon and Reisberg, 1999)

Question 2-5:



2. Since active dementia patients possess better rest-activity rhythm than sedentary patients by

actigraphical measures and nursing staff classification (Laura et al., 2008), it will be better if the

authors provide related information about number of ambulatory patients in different diagnostic

subtypes.

3. Is there any difference in incidence of sleep disorder between CBD and other FTD? Previous

study suggests that temporal variant FTD (tvFTD, with postmortem diagnosis) rather than

frontal variant FTD showed a higher prevalence of sleep disorders than AD (Liu et al., 2004).

4. In the study, duration of illness of AD was significantly different from that of FTD. What was

the role of this difference in the final result?

5. The GDS is most relevant for people who have Alzheimer's disease, since some other types of

dementia (i.e. FTD) usually not always include memory loss. It maybe not so appropriate to

define the dementia stage of FTD patients with GDS.

1.3 Apparatus and variables

1.3. 1 Apparatus

Physiological rhythms were studied for 72 hours, beginning at noon on the first study day, using

ambulatory monitors. Motor activity was recorded using an AM-16 activity monitor (AMI, Ardsley,

NY).

Temperature was measured by a temperature sensitive thermistor (Series 400; YSI Inc, Yellow Springs,

Ohio), placed in the rectum to a depth of 10 cm and connected to an ambulatory temperature monitor

(Mini-Logger; Mini-Mitter Corp, Sun River, Ore).

All temperature and activity records were at least 80% complete.

Physiological data were recorded 1.74±0.21 (mean±SD) years before death and autopsy.

Question 6-8:

6. About actigraphical measured physiological rhythms, may 72 hours be too short?

7. Is it difficult to put a depth of 10 cm probe into the rectum of dementia patients for 72 hours?

8. What is Physiological data which has been recorded 1.74±0.21 years? I’m sorry for failing to

find it form the text.

1.3.2 Variables

M10: the mean activity counts per hour of the 10 most active hours in the 24-hour period.

L5: the mean activity counts per hour of the 5 least active hours in the 24-hour period.



Interdaily stability: measure day-to-day stability of the rhythm.

Intradaily variability: assesses the period-to-period variability of the rhythm.

Mesor: the point around which the model oscillates.

Relative amplitude:amplitude per mesor. Amplitude= the distance from the mesor to the peak.

Acrophase: the time of the model peak.

Goodness-of-fit: the square of the least squares correlation [R2] of the model.

2. Results of the article

2.1 Activity level

2.1.1 Mean diurnal activity was significantly higher in AD patients than in FTD patients, although both

were significantly lower than control levels.

2.1.2 Noctoturnal activity levels were significantly higher in AD patients than in controls.

2.1.3 The M10 levels were significantly reduced in both dementia groups, with FTD patients having

lower levels than AD patients.

2.1.4 The L5 was significantly elevated in the AD group over both FTD and controls.

My impression is: AD patients are more active in daytime comparing to FTD patients with more restless

nights.

Question 9:

How about the onset time of M10 and L5?

2.2 Activity rhythm

2.2.1 Interdaily stability was lower in both diagnostic groupings than in controls, and there were no

differences between the 2 diagnostic groups.

2.2.2 Intradaily variability was higher in the FTD group than in both controls and AD.

My impression is: FTD patients showed increased fragmentation of activity than AD patients.



2.3 Cosinor analyses of activity and temperature rhythms

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).

Question 10:

Although activity or temperature data lacking a demonstrable circadian rhythm were excluded from

further cosinor analysis, they were not excluded from analysis of activity level and activity rhythm. We

could image that the patients lack of activity rhythm may be the mort severe dementia and showed the

most sedentary situation.

2.3.1 The mesor of the activity rhythm was lower in both dementia diagnoses than in the control group,

and the mesor in FTD patients was lower than the mesor in AD patients.

2.3.2 Relative amplitude was similar in the 3 groups.

2.3.3 The phase time was significantly delayed in AD and advanced in the FTD group when compared

with the normal elderly group.

2.3.4 Correlation of the data to the model was lower in the FTD group when compared with both control

and AD groups.

2.3.5 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.

2.3.6 The phase of the temperature rhythm was significantly delayed in the AD patients but not in the

FTD patients.

My impression is: FTD patients showed lower activity rhythm than AD patients.

3. Discussion and conclusions of the article

3.1 Discussion

3.1.1 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.



3.1.2 The increase in the L5 in AD demonstrates that this increase in nocturnal activity cannot be

entirely explained by delayed activity phase.

Question 11:

To be contrary, could delayed activity phase in AD be explained by increase in the L5?

The L5 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.

Question 12:

Why I can not find robust cause-effect relationship between two sentences?(P358, 2nd line)

3.1.3 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. 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.

Measurements of phase of the circadian rhythm of core-body temperature provide information about the

state of internal timekeeping relative to the environment. 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 subjects with AD.

It is also possible that phase-delay in the rest-activity rhythm, perhaps caused by weakening of the sleep

homeostat, 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.

Question 13:

How to prove it (phase-delay in the rest-activity rhythm is causing phase-delay in the temperature

rhythm)?

3.1.4 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. (P358, 12th to last line)

Question 14:

Why I can not find logical relationship between two sentences?

3.1.5 Frontotemporal degeneration patients 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. 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.

3.2 Limitation and Future research

3.2.1 Only male dementia patients were studied. According to previous studies, women show different

patterns of sleep and circadian physiology during aging than men.

3.2.2 The advanced state of dementia in these subjects. Sleep disturbance can occur early during the

course of a dementing illness.

3.2.3 A constant routine protocol would allow for more precise quantification of endogenous circadian

phase and amplitude of core body temperature.

3.2.4 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.

3.2.5 Further work is needed to understand the nature of the rest-activity rhythm disturbance in FTD.

3.3 Conclusions

3.3.1 The study supports the hypothesis that central changes cause the observed, rhythmical changes

identified previously in AD and FTD.

3.3.2 Testing circadian disturbances may be an effective way to differentially diagnose these 2

degenerative dementias.



3.3.3 Localizing the exact nature of disturbance could lead to new treatments for these debilitating

symptoms of dementia.

Comments

1. The main useful find is :

a. FTD patients show a fundamentally different type of circadian abnormality than do AD

patients.

b. In AD, both central pacemaker and behavioral expression are altered. While, the central

pacemaker seems to be functioning normally in FTD. Therefore, chronobiological

treatments, aimed at the SCN and the endogenous circadian rhythm may be effective in

treating the behavioral disturbances in AD, but not FTD.

2. Although the study was conducted with small sample size (FTD=9) and short observation time

(72 hours), the postmortem autopsy makes the diagnosis credible. And the small sample size of

FTD group may due to comparatively low incidence.

3. However, the severity of dementia in the subjects needs to be further defined, and therefore

limit the extrapolation of the result. And since the GDS is not suitable for FTD, negative finding

in FTD group should be interpreted cautiously

4. Due to the difference in sleep disorders, classification of FTD is necessary. Future research may

be needed to distinguish rest-activity disturbances between different subtype of FTD and AD.

Article revie...2010/07/29 · 1 牧本研究室抄読会 2010-7-29 担当：Catheline Article...

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