Armodafinil

improves

wakefulness

and

long-term

episodic

memory

in

nCPAP-adherent

patients

with

excessive

sleepiness

associated

with

obstructive

sleep

apnea

Residual

excessive

sleepiness

-LRB-

ES

-RRB-

and

impaired

cognition

can

occur

despite

effective

and

regular

nasal

continuous

positive

airway

pressure

-LRB-

nCPAP

-RRB-

therapy

in

some

patients

with

obstructive

sleep

apnea

-LRB-

OSA

-RRB-

A

pooled

analysis

of

two

randomized

double-blind

studies

in

nCPAP-adherent

patients

with

ES

associated

with

OSA

evaluated

the

effect

of

armodafinil

on

wakefulness

and

cognition

Three

hundred

and

ninety-one

patients

received

armodafinil

-LRB-

or

mg

-RRB-

and

patients

received

placebo

once

daily

for

weeks

Efficacy

assessments

included

the

Maintenance

of

Wakefulness

Test

-LRB-

MWT

-RRB-

Cognitive

Drug

Research

cognitive

performance

battery

Epworth

Sleepiness

Scale

and

Brief

Fatigue

Inventory

Adverse

events

were

monitored

Armodafinil

increased

mean

MWT

sleep

latency

from

baseline

to

final

visit

by

min

vs

a

decrease

of

min

with

placebo

-LRB-

P

-RRB-

Compared

with

placebo

armodafinil

significantly

improved

quality

of

episodic

secondary

memory

-LRB-

P

-RRB-

and

patients

ability

to

engage

in

activities

of

daily

living

-LRB-

P

-RRB-

and

reduced

fatigue

-LRB-

P

-RRB-

The

most

common

adverse

events

were

headache

nausea

and

insomnia

Armodafinil

did

not

adversely

affect

desired

nighttime

sleep

and

nCPAP

use

remained

high

-LRB-

approximately

h/night

-RRB-

Adjunct

treatment

with

armodafinil

significantly

improved

wakefulness

long-term

memory

and

patients

ability

to

engage

in

activities

of

daily

living

in

nCPAP-adherent

individuals

with

ES

associated

with

OSA

Armodafinil

also

reduced

patient-reported

fatigue

and

was

well

tolerated

Introduction

Obstructive

sleep

apnea

-LRB-

OSA

-RRB-

syndrome

includes

excessive

sleepiness

-LRB-

ES

-RRB-

fatigue

sleep

fragmentation

impaired

alertness

cognitive

dysfunction

and

mood

disturbances

-LSB-

-RSB-

OSA

is

typically

characterized

by

recurrent

complete

or

partial

airway

collapse

during

sleep

resulting

in

frequent

apnea

and

hypopneic

events

lasting

at

least

s

-LSB-

-RSB-

Although

the

reported

prevalence

of

OSA

in

the

general

population

varies

as

a

function

of

diagnostic

criteria

-LSB-

-RSB-

OSA

syndrome

has

been

estimated

to

occur

in

and

of

middle-aged

North

American

men

and

women

respectively

-LSB-

-RSB-

OSA

can

lead

to

serious

medical

social

and

public

safety

consequences

and

patients

are

at

an

increased

risk

for

cardiovascular

disease

-LSB-

-RSB-

and

motor

vehicle

and

occupational

accidents

-LSB-

-RSB-

Quality

of

life

and

social

functioning

are

also

significantly

impaired

in

this

patient

population

-LSB-

-RSB-

Fatigue

in

particular

can

contribute

to

reduced

quality

of

life

-LSB-

-RSB-

thus

the

assessment

of

patient-rated

fatigue

is

an

important

outcome

to

evaluate

and

monitor

in

patients

with

OSA

Nasal

continuous

positive

airway

pressure

-LRB-

nCPAP

-RRB-

therapy

is

the

recommended

standard

of

care

for

treating

patients

with

moderate

to

severe

OSA

-LSB-

-RSB-

In

a

comprehensive

review

of

clinical

studies

nCPAP

therapy

was

shown

to

effectively

reduce

objective

and

subjective

measures

of

sleepiness

and

improve

quality

of

life

in

patients

with

moderate

and

severe

OSA

-LSB-

-RSB-

However

despite

receiving

adequate

nCPAP

therapy

half

of

patients

with

OSA

still

experience

residual

ES

as

measured

by

objective

assessments

as

well

as

impairments

in

mood

or

cognition

-LSB-

-RSB-

Cognitive

impairment

in

patients

with

OSA

is

characterized

by

deficits

in

attention

learning

and

memory

and

executive

function

-LRB-

planning

and

problem

solving

-RRB-

and

may

persist

despite

nCPAP

therapy

-LSB-

-RSB-

A

review

of

the

literature

suggests

that

while

nCPAP

therapy

can

substantially

improve

quality

of

life

for

patients

with

OSA

it

has

a

smaller

effect

on

improving

cognitive

performance

-LSB-

-RSB-

Modafinil

a

racemic

mixture

consisting

of

equal

amounts

of

R

and

S-enantiomers

has

been

shown

to

improve

wakefulness

in

patients

with

OSA

who

experience

residual

ES

despite

regular

nCPAP

use

-LSB-

-RSB-

Pharmacokinetic

studies

have

shown

that

the

half-life

of

R-modafinil

-LRB-

h

-RRB-

is

significantly

longer

than

the

half-life

of

S-modafinil

-LRB-

h

-RRB-

-LSB-

-RSB-

Armodafinil

has

higher

plasma

concentrations

later

in

the

day

compared

to

modafinil

on

a

milligram-to-milligram

basis

and

improves

healthy

subjects

wakefulness

and

ability

to

sustain

attention

for

a

longer

period

of

time

compared

with

modafinil

-LSB-

-RSB-

Armodafinil

has

also

recently

been

shown

to

improve

wakefulness

in

patients

with

ES

associated

with

narcolepsy

in

a

double-blind

placebo-controlled

study

-LSB-

-RSB-

Recent

findings

from

two

double-blind

placebo-controlled

studies

of

similar

design

indicate

that

armodafinil

improved

wakefulness

and

overall

clinical

condition

in

nCPAP-adherent

patients

with

OSA

and

residual

ES

-LSB-

-RSB-

In

the

present

pooled

analysis

of

the

two

OSA

studies

-LSB-

-RSB-

the

effects

on

wakefulness

cognition

and

fatigue

and

the

safety

and

tolerability

of

armodafinil

compared

with

placebo

were

evaluated

in

OSA

patients

adherent

to

nCPAP

therapy

Materials

and

methods

Study

design

and

procedures

Data

from

two

multicenter

double-blind

placebo-controlled

parallel-group

clinical

studies

were

pooled

for

analysis

The

pooling

of

these

data

was

based

on

similarities

in

patient

population

study

design

and

treatment

duration

in

the

two

studies

-LSB-

-RSB-

One

study

was

conducted

in

centers

across

the

USA

Australia

Russia

Germany

and

France

-LSB-

-RSB-

and

the

other

study

was

conducted

in

centers

across

the

USA

and

Canada

-LSB-

-RSB-

The

study

protocols

were

approved

by

an

Independent

Ethics

Committee

or

Institutional

Review

Board

at

each

center

Both

studies

were

conducted

in

accordance

with

the

Good

Clinical

Practice

Consolidated

Guideline

-LSB-

-RSB-

and

national

and

local

laws

and

regulations

Patients

were

randomized

to

receive

armodafinil

mg

-LRB-

n

-RRB-

or

placebo

-LRB-

n

-RRB-

daily

in

the

first

study

-LSB-

-RSB-

and

armodafinil

-LRB-

n

-RRB-

or

mg/day

-LRB-

n

-RRB-

or

placebo

-LRB-

n

-RRB-

in

the

second

study

-LSB-

-RSB-

Study

drugs

were

initiated

with

a

dose

of

mg/day

on

day

and

then

increased

in

increments

of

mg

starting

on

day

and

every

days

thereafter

until

the

assigned

dose

was

reached

-LRB-

i.e.

mg/day

on

day

for

both

studies

or

mg/day

on

day

for

the

second

study

-RRB-

The

study

drugs

were

taken

once

daily

in

the

morning

-LRB-

before

and

approximately

min

before

breakfast

-RRB-

Monitoring

of

patients

compliance

with

study

drug

administration

was

the

responsibility

of

the

investigator

at

each

center

and

was

assessed

by

completed

study

drug

accountability

records

and

reviews

of

patient

diaries

nCPAP

use

at

home

was

also

monitored

objectively

by

investigators

at

each

visit

to

the

study

center

using

the

REMstar

Auto

CPAP

System

-LRB-

Respironics

Murrysville

PA

-RRB-

The

REMstar

Auto

CPAP

System

was

used

in

CPAP

mode

Patient

selection

criteria

Methods

for

selecting

patients

in

both

studies

have

been

described

previously

-LSB-

-RSB-

Men

and

women

to

years

of

age

with

a

current

diagnosis

of

OSA

as

defined

by

the

International

Classification

of

Sleep

Disorders

-LSB-

-RSB-

were

included

in

both

studies

Patients

were

at

least

moderately

ill

-LRB-

Clinical

Global

Impression

of

Severity

of

Illness

rating

greater

than

or

equal

to

-RRB-

-LSB-

-RSB-

and

had

a

complaint

of

ES

Patients

were

eligible

if

ES

was

determined

to

be

pathological

based

on

an

Epworth

Sleepiness

Scale

-LRB-

ESS

-RRB-

score

greater

than

or

equal

to

-LSB-

-RSB-

All

patients

were

receiving

stable

-LRB-

greater

than

or

equal

to

weeks

-RRB-

and

effective

nCPAP

therapy

on

a

regular

basis

-LRB-

greater

than

or

equal

to

h

per

night

on

greater

than

or

equal

to

of

nights

-RRB-

during

the

evaluation

period

The

CPAP

use

was

monitored

using

the

REMstar

Auto

CPAP

System

Effectiveness

of

therapy

was

determined

by

an

apnea

hypopnea

index

-LRB-

AHI

-RRB-

less

than

or

equal

to

ten

events

per

hour

on

nighttime

polysomnography

-LRB-

PSG

-RRB-

Patient

exclusion

criteria

Patients

were

excluded

if

they

had

any

of

the

following

a

diagnosis

of

a

sleep

disorder

other

than

OSA

symptoms

of

ES

associated

with

a

clinically

significant

uncontrolled

medical

or

psychiatric

condition

as

determined

by

the

investigator

any

disorder

that

might

interfere

with

drug

absorption

distribution

metabolism

or

excretion

a

history

of

drug

or

alcohol

abuse

as

determined

by

the

Diagnostic

and

Statistical

Manual

of

Mental

Disorders

IV

criteria

-LSB-

-RSB-

or

by

a

positive

result

from

the

urine

drug

screen

given

at

screening

and

again

at

the

final

visit

caffeine

consumption

greater

than

mg/day

or

a

clinically

significant

sensitivity

to

central

nervous

system

stimulants

or

modafinil

Women

who

were

pregnant

or

breast

feeding

were

also

excluded

The

use

of

any

substance

that

could

affect

wakefulness

or

sleepiness

-LRB-

e.g.

modafinil

sodium

oxybate

melatonin

lithium

St.

John

's

wort

methylphenidate

amphetamines

pemoline

antipsychotic

agents

benzodiazepines

zolpidem

anticonvulsants

or

barbiturates

-RRB-

use

of

other

excluded

agents

-LRB-

e.g.

monoamine

oxidase

inhibitors

anticoagulants

-RRB-

use

of

clinically

significant

amounts

of

nonprescription

drugs

within

days

of

screening

and

use

of

investigational

drugs

within

month

of

screening

was

prohibited

All

patients

provided

written

informed

consent

before

participation

in

these

studies

and

were

compensated

for

their

participation

Assessments

Efficacy

assessments

Efficacy

assessments

were

performed

for

both

studies

at

baseline

and

weeks

and

The

primary

efficacy

variables

in

the

two

individual

studies

were

the

change

from

baseline

to

final

visit

-LRB-

week

or

last

postbaseline

measurement

-RRB-

in

mean

Maintenance

of

Wakefulness

Test

-LRB-

MWT

-RRB-

-LSB-

-RSB-

sleep

latency

averaged

across

the

first

four

tests

and

the

proportion

of

patients

with

at

least

minimal

improvement

on

the

Clinical

Global

Impression

of

Change

-LRB-

CGI-C

-RRB-

-LSB-

-RSB-

The

MWT

was

conducted

as

six

separate

sessions

at

and

Sleep

latency

was

defined

as

the

time

to

onset

of

the

first

of

three

consecutive

epochs

of

stage

sleep

or

the

time

to

onset

of

any

epoch

of

stages

and

sleep

or

rapid

eye

movement

sleep

-LSB-

-RSB-

Sleep

latencies

were

averaged

across

the

first

four

tests

-LRB-

-RRB-

and

the

last

three

tests

-LRB-

-RRB-

to

distinguish

between

early

and

late-day

effects

respectively

The

proportion

of

patients

with

at

least

a

minimal

improvement

on

the

CGI-C

was

assessed

to

determine

patients

overall

clinical

improvement

in

the

individual

studies

however

these

data

were

not

poolable

for

this

analysis

because

of

a

substantial

difference

in

the

percentage

of

responders

to

placebo

between

the

two

studies

The

Cognitive

Drug

Research

-LRB-

CDR

-RRB-

battery

of

tests

-LSB-

-RSB-

was

administered

by

computer

as

six

separate

sessions

conducted

at

and

The

CDR

battery

includes

five

memory

tests

-LRB-

immediate

word

recall

delayed

word

recall

numeric

working

memory

word

recognition

and

picture

recognition

-RRB-

and

three

attention

tests

-LRB-

simple

reaction

time

choice

reaction

time

and

digit

vigilance

-RRB-

Two

composite

factors

are

derived

from

the

memory

tests

in

the

CDR

quality

of

episodic

secondary

memory

a

measure

of

long-term

memory

that

measures

the

ability

to

recall

verbal

and

visual

information

and

speed

of

memory

which

assesses

the

time

it

takes

to

decide

whether

information

is

held

in

memory

Two

composite

factors

are

derived

from

the

CDR

for

attention

power

of

attention

which

measures

the

ability

to

focus

attention

and

avoid

distraction

-LRB-

concentration

-RRB-

and

continuity

of

attention

which

measures

the

ability

to

sustain

attention

-LRB-

vigilance

-RRB-

Similar

to

the

MWT

the

CDR

scores

were

averaged

across

the

first

four

test

sessions

-LRB-

-RRB-

and

the

last

three

test

sessions

-LRB-

-RRB-

to

assess

cognitive

effects

on

early

and

late-day

measurements

The

patients

ability

to

engage

in

daily

activities

was

assessed

at

each

visit

by

the

ESS

-LSB-

-RSB-

ESS

total

scores

range

from

to

with

higher

scores

indicating

greater

sleepiness

An

ESS

score

greater

than

or

equal

to

indicates

pathological

sleepiness

-LSB-

-RSB-

The

severity

and

impact

of

patient-rated

fatigue

on

daily

functioning

were

assessed

at

each

visit

by

the

nine-item

Brief

Fatigue

Inventory

-LRB-

BFI

-RRB-

-LSB-

-RSB-

and

were

based

on

changes

in

global

fatigue

-LRB-

average

of

all

nine

questions

-RRB-

and

worst

fatigue

in

the

past

h

-LRB-

item

-RRB-

The

rating

scale

for

the

BFI

ranges

from

-LRB-

no

fatigue

-RRB-

to

-LRB-

as

bad

as

you

can

imagine

-RRB-

A

score

of

greater

than

or

equal

to

for

either

global

fatigue

or

worst

fatigue

in

the

past

h

is

indicative

of

severe

fatigue

Both

the

ESS

and

BFI

were

administered

before

the

first

MWT

session

-LRB-

-RRB-

at

each

visit

Safety

and

tolerability

assessments

Adverse

events

were

monitored

and

recorded

by

the

study

investigators

at

each

center

throughout

both

studies

Clinical

laboratory

tests

-LRB-

blood

chemistry

hematology

urinalysis

-RRB-

vital

signs

-LRB-

resting

heart

rate

and

systolic

and

diastolic

blood

pressure

and

h

postadministration

-RRB-

and

electrocardiograms

were

obtained

at

screening

baseline

and

weeks

and

Physical

examinations

were

performed

at

baseline

and

week

Patients

use

of

nCPAP

was

monitored

at

least

weeks

before

baseline

and

throughout

both

studies

using

the

Respironics

REMstar

Auto

CPAP

system

Effect

on

nighttime

sleep

was

determined

by

PSG

which

was

performed

the

night

immediately

after

the

measurement

of

daytime

MWT

during

the

second

screening

visit

and

the

final

visit

The

PSG

was

conducted

for

h

starting

within

min

of

the

patient

's

usual

bedtime

but

not

earlier

than

Clinically

significant

elevations

in

resting

systolic

and

diastolic

blood

pressure

were

defined

a

priori

as

greater

than

or

equal

to

mmHg

with

an

increase

of

greater

than

or

equal

to

and

greater

than

or

equal

to

mmHg

with

an

increase

of

greater

than

or

equal

to

respectively

Patients

with

worsening

hypertension

included

those

who

had

a

history

of

hypertension

at

baseline

and

who

started

new

antihypertensive

medication

and/or

increased

the

dose

of

previously

used

antihypertensive

medication

during

the

studies

Patients

with

newly

diagnosed

hypertension

included

those

who

had

no

history

of

hypertension

at

baseline

and

who

started

antihypertensive

medication

during

the

studies

Patients

at

risk

for

hypertension

included

those

who

had

at

least

two

clinically

significant

elevations

in

blood

pressure

readings

between

baseline

and

final

visit

Statistical

analysis

Descriptive

statistics

were

used

to

summarize

continuous

and

categorical

demographic

variables

Efficacy

assessments

were

analyzed

at

weeks

and

using

observed

cases

and

at

final

visit

-LRB-

week

or

last

postbaseline

measurement

-RRB-

using

the

last

observation

carried

forward

approach

Efficacy

analyses

included

randomized

patients

who

received

at

least

one

dose

of

study

drug

and

had

a

baseline

measurement

with

at

least

one

postbaseline

measurement

on

the

MWT

and

CGI-C

Safety

and

tolerability

analyses

included

all

randomized

patients

who

received

at

least

one

dose

of

study

drug

All

efficacy

assessments

were

analyzed

by

analysis

of

variance

-LRB-

ANOVA

-RRB-

with

treatment

and

study

as

factors

Tests

of

poolability

for

all

continuous

efficacy

variables

across

the

two

studies

were

conducted

using

an

ANOVA

with

treatment

and

study

and

treatment

by

study

interaction

as

factors

Vital

signs

and

data

from

nighttime

PSG

were

analyzed

by

Wilcoxon

rank-sum

test

For

nCPAP

use

the

change

from

baseline

to

on-treatment

values

was

analyzed

using

one-way

ANOVA

All

statistical

tests

were

two-tailed

and

the

level

of

significance

was

used

Results

Patient

demographics

and

disease

characteristics

Of

patients

randomized

were

included

in

the

safety

analysis

and

were

evaluable

for

efficacy

-LRB-

Fig.

-RRB-

Patient

demographics

and

disease

characteristics

for

all

patients

in

the

safety

analyses

are

summarized

in

Table

The

mean

body

mass

index

was

Patients

reported

high

nightly

nCPAP

usage

-LRB-

mean

-LSB-

SD

-RSB-

hours

of

nightly

use

armodafinil

-LSB-

-RSB-

h

placebo

-LSB-

-RSB-

h

-RRB-

The

nCPAP

therapy

was

effective

as

shown

by

mean

-LRB-

SD

-RRB-

AHI

values

of

-LRB-

-RRB-

and

-LRB-

-RRB-

events/h

in

the

armodafinil

and

placebo

groups

respectively

Overall

of

patients

had

a

history

of

hypertension

at

baseline

Fig.

dispositionTable

demographics

and

baseline

characteristicsCharacteristicArmodafinil

-LRB-

n

-RRB-

Placebo

-LRB-

n

-RRB-

Age

-LRB-

years

-RRB-

Mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Sex

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Race

n

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Weight

-LRB-

kg

-RRB-

Mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

BMI

-LRB-

-RRB-

Mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

CGI-S

n

-LRB-

-RRB-

Moderately

-LRB-

-RRB-

-LRB-

-RRB-

Markedly

severely

or

extremely

-LRB-

-RRB-

-LRB-

-RRB-

nCPAP

-LRB-

h

-RRB-

Mean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

AHIMean

-LRB-

SD

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

History

of

hypertensionn

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

AHI

Apnea

hypopnea

index

BMI

body

mass

index

CGI-S

Clinical

Global

Impression

of

Severity

of

Illness

nCPAP

nasal

continuous

positive

airway

pressure

Effects

on

wakefulness

Mean

-LRB-

SD

-RRB-

sleep

latency

at

baseline

across

the

first

four

MWTs

-LRB-

-RRB-

was

-LRB-

-RRB-

and

-LRB-

-RRB-

min

for

the

armodafinil

and

placebo

groups

respectively

At

all

study

visits

armodafinil

significantly

improved

mean

sleep

latency

across

the

first

four

MWTs

compared

with

placebo

-LRB-

Fig.

-RRB-

The

mean

change

from

baseline

in

sleep

latency

at

final

visit

was

min

for

the

armodafinil

group

compared

with

min

for

the

placebo

group

-LRB-

P

-RRB-

Fig.

-LRB-

SEM

-RRB-

change

from

baseline

in

sleep

latency

from

the

Maintenance

of

Wakefulness

Test

-LRB-

MWT

-RRB-

a

Sleep

latencies

averaged

across

the

first

four

tests

-LRB-

-RRB-

b

Sleep

latencies

averaged

across

the

last

three

tests

-LRB-

-RRB-

Armodafinil

also

improved

patients

ability

to

maintain

late-day

wakefulness

-LRB-

MWTs

at

-RRB-

compared

with

placebo

-LRB-

Fig.

-RRB-

Mean

-LRB-

SD

-RRB-

sleep

latency

at

baseline

across

the

last

three

MWTs

was

-LRB-

-RRB-

and

-LRB-

-RRB-

min

for

the

armodafinil

and

placebo

groups

respectively

The

mean

change

from

baseline

in

sleep

latency

at

final

visit

was

min

for

the

armodafinil

group

compared

with

min

for

the

placebo

group

-LRB-

P

-RRB-

Effects

on

memory

and

attention

Compared

with

placebo

armodafinil

significantly

improved

the

quality

of

episodic

secondary

memory

across

the

first

four

tests

-LRB-

-RRB-

at

all

study

visits

-LRB-

P

Fig.

-RRB-

The

mean

-LRB-

SD

-RRB-

change

from

baseline

in

quality

of

episodic

secondary

memory

at

final

visit

was

-LRB-

-RRB-

U

for

the

armodafinil

group

compared

with

-LRB-

-RRB-

U

for

the

placebo

group

-LRB-

P

-RRB-

Differences

between

the

treatment

groups

did

not

achieve

statistical

significance

at

the

final

visit

for

speed

of

memory

power

of

attention

or

continuity

of

attention

across

the

first

four

tests

Fig.

-LRB-

SEM

-RRB-

change

from

baseline

in

quality

of

episodic

secondary

memory

a

Scores

averaged

across

the

first

four

tests

-LRB-

-RRB-

b

Scores

averaged

across

last

three

tests

-LRB-

-RRB-

Across

the

later

three

tests

of

the

day

-LRB-

-RRB-

the

difference

in

the

quality

of

episodic

secondary

memory

was

statistically

significant

at

week

for

armodafinil

compared

with

placebo

-LRB-

P

Fig.

-RRB-

with

a

trend

toward

significance

at

week

-LRB-

P

-RRB-

The

difference

between

treatment

groups

was

not

statistically

significant

at

the

final

visit

for

the

quality

of

episodic

secondary

memory

There

were

no

significant

changes

from

baseline

to

final

visit

between

the

armodafinil

and

placebo

groups

for

speed

of

memory

power

of

attention

or

continuity

of

attention

across

the

last

three

tests

Effects

on

patients

ability

to

engage

in

activities

The

mean

-LRB-

SD

-RRB-

ESS

scores

were

high

at

baseline

-LRB-

-LSB-

-RSB-

and

-LSB-

-RSB-

for

the

armodafinil

and

placebo

groups

respectively

-RRB-

despite

the

high

nCPAP

use

as

shown

in

Table

Compared

with

placebo

treatment

with

armodafinil

significantly

improved

patients

ability

to

engage

in

activities

of

daily

living

-LRB-

ESS

-RRB-

at

all

visits

-LRB-

P

Fig.

-RRB-

Nearly

half

of

all

patients

-LRB-

-RRB-

in

the

armodafinil

group

responded

to

treatment

-LRB-

total

ESS

score

less

than

at

final

visit

-RRB-

compared

with

in

the

placebo

group

Fig.

-LRB-

SEM

-RRB-

change

from

baseline

in

Epworth

Sleepiness

Scale

total

score

Effects

on

fatigue

The

mean

-LRB-

SD

-RRB-

scores

for

global

fatigue

from

the

BFI

at

baseline

were

-LRB-

-RRB-

and

-LRB-

-RRB-

for

the

armodafinil

and

placebo

groups

respectively

Armodafinil

significantly

improved

global

fatigue

at

all

visits

compared

with

placebo

-LRB-

P

Fig.

-RRB-

Mean

scores

for

worst

fatigue

in

the

past

h

from

the

BFI

at

baseline

were

nearly

identical

for

the

armodafinil

and

placebo

groups

-LRB-

-LSB-

-RSB-

and

-LSB-

-RSB-

respectively

-RRB-

and

indicated

severe

fatigue

-LRB-

score

greater

than

or

equal

to

-RRB-

Armodafinil

significantly

improved

scores

for

worst

fatigue

in

the

past

h

at

weeks

and

and

at

the

final

visit

-LRB-

P

vs

placebo

Fig.

-RRB-

with

a

trend

toward

significance

at

week

-LRB-

P

vs

placebo

-RRB-

Fig.

-LRB-

SEM

-RRB-

change

from

baseline

in

fatigue

a

Global

fatigue

b

Worst

fatigue

in

the

past

h.

BFI

Brief

Fatigue

Inventory

Safety

and

tolerability

Armodafinil

was

well

tolerated

with

a

low

incidence

of

adverse

events

most

of

which

were

mild

to

moderate

in

nature

Headache

was

the

most

commonly

reported

adverse

event

defined

as

occurring

in

greater

than

or

equal

to

in

either

group

-LRB-

Table

-RRB-

Serious

adverse

events

were

considered

by

the

investigator

unlikely

to

be

or

not

related

to

armodafinil

-LRB-

ulcerative

colitis

n

migraine

n

worsening

of

Axis

II

disorder

and

mood

disorder

n

duodenal

ulcer

hemorrhage

n

-RRB-

One

serious

adverse

event

was

reported

in

the

placebo

group

-LRB-

gastroesophageal

reflux

disease

-RRB-

The

most

frequently

occurring

adverse

events

that

led

to

discontinuation

among

patients

receiving

armodafinil

were

headache

-LRB-

n

-RRB-

and

nausea

-LRB-

n

-RRB-

Table

events

occurring

in

of

patientsAdverse

event

n

-LRB-

-RRB-

Armodafinil

-LRB-

n

-RRB-

Placebo

-LRB-

n

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

There

were

no

clinically

significant

changes

from

baseline

to

final

visit

in

either

the

armodafinil

group

or

the

placebo

group

for

laboratory

values

electrocardiogram

parameters

or

physical

examinations

There

were

also

no

meaningful

changes

-LRB-

clinical

or

statistical

-RRB-

from

baseline

to

final

visit

for

systolic

blood

pressure

-LRB-

-LSB-

-RSB-

mmHg

for

armodafinil

vs

-LSB-

-RSB-

mmHg

for

placebo

-RRB-

diastolic

blood

pressure

-LRB-

-LSB-

-RSB-

mmHg

for

armodafinil

vs

-LSB-

-RSB-

mmHg

for

placebo

-RRB-

and

heart

rate

-LRB-

-LSB-

-RSB-

bpm

for

armodafinil

vs

-LSB-

-RSB-

bpm

for

placebo

-RRB-

The

incidence

of

patients

with

newly

diagnosed

hypertension

was

less

than

in

the

armodafinil

group

and

less

than

in

the

placebo

group

The

proportion

of

patients

at

risk

for

hypertension

was

similar

for

both

treatment

groups

-LRB-

of

patients

armodafinil

group

of

patients

placebo

group

-RRB-

The

incidence

of

patients

with

worsening

hypertension

was

of

patients

in

the

armodafinil

group

and

of

patients

in

the

placebo

group

nCPAP

use

remained

high

-LRB-

approximately

h/night

-RRB-

throughout

both

of

the

studies

The

duration

of

nCPAP

use

at

final

visit

was

reduced

from

baseline

by

a

mean

-LRB-

SD

-RRB-

of

-LRB-

-RRB-

h

with

armodafinil

compared

with

-LRB-

-RRB-

h

with

placebo

-LRB-

a

between-group

difference

of

about

min

P

-RRB-

At

final

visit

AHI

values

remained

low

and

were

comparable

between

the

armodafinil

and

placebo

groups

-LRB-

P

vs

placebo

-RRB-

In

addition

there

were

no

significant

changes

from

baseline

in

nocturnal

PSG

sleep

variables

between

the

armodafinil

and

placebo

groups

-LRB-

P

Table

-RRB-

Table

polysomnography

parametersaVariable

-LRB-

units

-RRB-

mean

-LRB-

SD

-RRB-

Armodafinil

-LRB-

n

-RRB-

Placebo

-LRB-

n

-RRB-

BaselineFinal

VisitBaselineFinal

VisitLatency

to

persistent

sleep

-LRB-

min

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Number

of

arousals

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Number

of

awakenings

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Sleep

efficiency

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Wake

after

sleep

onset

-LRB-

min

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Stage

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Stage

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Stage

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

REM

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

REM

Rapid

eye

movementaNo

significant

differences

between

baseline

and

final

visit

were

observed

Discussion

Recognizing

and

effectively

managing

ES

in

patients

with

OSA

is

essential

for

clinicians

because

of

the

profound

impact

that

ES

has

on

the

patients

their

families

and

coworkers

and

the

general

public

-LRB-

e.g.

increased

risk

of

traffic

accidents

-RRB-

-LSB-

-RSB-

Without

appropriate

treatment

ES

adversely

affects

cognitive

-LSB-

-RSB-

occupational

-LSB-

-RSB-

and

social

functioning

-LSB-

-RSB-

Several

studies

evaluated

in

a

comprehensive

review

-LSB-

-RSB-

have

shown

that

there

is

general

improvement

in

wakefulness

with

nCPAP

therapy

especially

in

patients

with

more

severe

OSA

Nonetheless

residual

ES

can

persist

even

after

effective

nCPAP

treatment

-LSB-

-RSB-

suggesting

that

there

is

need

for

adjunctive

therapy

to

treat

ES

in

these

patients

The

present

study

re-evaluates

the

findings

from

two

separate

studies

on

the

effects

of

armodafinil

in

patients

with

refractory

ES

associated

with

OSA

and

provides

additional

information

regarding

secondary

analyses

for

which

the

individual

studies

may

not

have

had

adequate

statistical

power

In

the

individual

studies

-LSB-

-RSB-

armodafinil

was

shown

to

significantly

improve

daytime

mean

sleep

latency

across

the

first

four

tests

on

the

MWT

and

overall

clinical

condition

as

assessed

by

the

CGI-C

In

the

pooled

analysis

armodafinil

significantly

improved

patients

ability

to

sustain

wakefulness

as

objectively

assessed

by

the

MWT

Improvements

in

mean

sleep

latency

were

observed

at

the

first

visit

at

week

and

were

maintained

throughout

the

remainder

of

the

study

The

lack

of

a

consistent

effect

of

armodafinil

on

wakefulness

across

the

last

three

MWTs

-LRB-

-RRB-

likely

reflects

the

high

mean

sleep

latency

-LRB-

approximately

min

-RRB-

at

these

times

Behavioral

effects

causing

poorer

performance

on

the

last

test

of

the

day

and

high

intertest

variability

in

sleep

latency

may

have

also

contributed

to

this

finding

-LSB-

-RSB-

The

individual

studies

also

included

the

clinician

's

subjective

assessment

of

treatment

effect

on

ES

the

CGI-C

Data

for

the

CGI-C

however

were

not

poolable

for

this

analysis

because

of

substantial

differences

in

the

proportion

of

patients

considered

responders

to

placebo

between

the

two

studies

In

the

individual

studies

the

proportion

of

patients

considered

responders

to

armodafinil

and

placebo

was

and

respectively

in

one

study

-LSB-

-RSB-

and

and

respectively

in

the

other

study

-LSB-

-RSB-

Cognitive

impairment

is

common

in

patients

with

OSA

-LSB-

-RSB-

Although

the

etiology

has

not

been

definitively

determined

decreased

cortical

activity

because

of

impaired

arousal

or

neuronal

damage

because

of

chronic

intermittent

hypoxia

are

possible

causes

-LSB-

-RSB-

It

is

not

yet

clear

what

additional

interventions

may

be

effective

in

restoring

cognitive

function

in

patients

with

OSA

Findings

from

studies

evaluating

the

effects

of

nCPAP

therapy

on

memory

and

attention

have

yielded

inconsistent

results

-LSB-

-RSB-

Unlike

the

findings

from

the

individual

armodafinil

OSA

studies

-LSB-

-RSB-

the

pooled

analysis

showed

that

adjunct

armodafinil

significantly

improves

long-term

memory

-LRB-

i.e.

quality

of

episodic

secondary

memory

-RRB-

at

all

study

visits

compared

with

placebo

indicating

that

treatment

was

associated

with

a

greater

ability

to

recall

verbal

and

visual

information

Interestingly

the

long-term

memory

benefit

occurred

independent

of

a

consistent

benefit

on

attention

and

concentration

It

is

important

to

note

that

the

CDR

composite

factors

in

both

of

the

individual

armodafinil

OSA

studies

were

secondary

efficacy

variables

Thus

although

results

from

the

pooled

analysis

provide

a

more

precise

estimate

of

the

effects

on

long-term

memory

further

studies

are

needed

to

determine

the

potential

role

of

armodafinil

in

improving

cognitive

function

in

nCPAP-adherent

patients

with

OSA

and

associated

ES

Armodafinil

significantly

improved

patients

ability

to

engage

in

activities

of

daily

living

at

all

visits

as

measured

by

the

ESS

The

patient

population

studied

in

this

pooled

analysis

had

severe

ES

-LRB-

mean

ESS

score

greater

than

-RRB-

despite

effective

and

regular

nCPAP

therapy

At

the

final

visit

and

of

patients

receiving

armodafinil

and

placebo

respectively

had

ESS

scores

less

than

indicating

that

nearly

half

of

patients

no

longer

had

pathological

sleepiness

with

adjunct

armodafinil

treatment

Fatigue

may

be

the

presenting

complaint

of

patients

with

ES

-LSB-

-RSB-

and

is

a

common

associated

symptom

-LSB-

-RSB-

Armodafinil

significantly

reduced

fatigue

a

result

similar

to

findings

from

the

individual

studies

-LSB-

-RSB-

Armodafinil

reduced

global

fatigue

from

a

baseline

value

of

to

a

final

visit

value

of

Similarly

worst

fatigue

in

the

past

h

was

reduced

from

a

baseline

of

to

at

final

visit

These

findings

indicate

that

armodafinil

significantly

reduced

the

severity

of

global

fatigue

and

worst

fatigue

in

the

past

h

to

the

mild-to-moderate

range

of

fatigue

-LRB-

BFI

score

less

than

-LSB-

-RSB-

-RRB-

This

pooled

analysis

shows

that

armodafinil

does

not

adversely

affect

nighttime

sleep

in

patients

with

OSA

even

with

its

longer-lasting

duration

of

action

compared

with

modafinil

on

a

milligram-to-milligram

basis

-LSB-

-RSB-

Armodafinil

was

well

tolerated

in

general

adverse

events

were

rated

as

mild

to

moderate

in

nature

although

some

patients

discontinued

because

of

adverse

events

There

were

some

minor

changes

in

vital

signs

however

these

effects

were

not

considered

to

be

clinically

significant

The

patient

population

selected

for

both

studies

was

verified

to

be

adherent

to

nCPAP

therapy

thus

the

primary

pathology

of

OSA

was

being

treated

in

an

appropriate

and

effective

manner

throughout

the

course

of

the

two

studies

At

the

final

visit

the

duration

of

nCPAP

use

had

decreased

minimally

from

baseline

compared

with

placebo

Average

nCPAP

use

remained

high

-LRB-

approximately

h/night

-RRB-

and

was

effective

-LRB-

i.e.

low

AHI

values

-RRB-

Adjunct

armodafinil

treatment

did

not

affect

arousals

Findings

from

the

present

pooled

analysis

are

limited

to

patients

with

OSA

who

have

residual

ES

despite

regular

and

effective

nCPAP

therapy

and

should

not

be

generalized

to

patients

with

OSA

who

are

not

receiving

adequate

nCPAP

therapy

or

are

not

using

it

regularly

Additionally

the

duration

of

treatment

in

these

studies

limits

the

applicability

of

observed

results

to

a

longer

period

of

treatment

It

should

be

recognized

that

armodafinil

does

not

treat

the

underlying

airway

obstruction

and

should

not

be

considered

a

replacement

for

nCPAP

therapy

in

patients

with

OSA

Further

research

is

needed

to

determine

the

role

armodafinil

may

have

in

improving

cognitive

function

and

whether

the

significant

reduction

in

fatigue

observed

in

the

pooled

analysis

will

contribute

toward

improved

quality

of

life

in

this

patient

population

In

conclusion

pooled

data

from

two

double-blind

placebo-controlled

studies

showed

that

once-daily

administration

of

armodafinil

significantly

improved

wakefulness

when

used

as

adjunct

therapy

in

nCPAP-adherent

patients

with

residual

ES

associated

with

OSA

The

effect

on

wakefulness

with

armodafinil

was

maintained

throughout

the

day

Importantly

adjunctive

treatment

with

armodafinil

was

associated

with

significant

improvements

in

long-term

memory

and

patients

ability

to

engage

in

daily

activities

Armodafinil

significantly

reduced

fatigue

in

the

studied

population

and

was

well

tolerated

B O B O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O B O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O

armodafinil fatigue sleepiness wakefulness


Measurement

of

overall

quality

of

life

in

nursing

homes

through

self-report

the

role

of

cognitive

impairment

Measuring

quality

of

life

is

a

necessity

for

adequate

interventions

This

paper

concerns

the

usefulness

of

six

self-report

measures

for

overall

quality

of

life

for

nursing

home

residents

with

various

levels

of

cognitive

impairment

It

was

investigated

which

proportion

of

residents

from

four

cognition

groups

could

complete

a

scale

and

internal

consistency

and

construct

validity

of

the

scales

were

studied

Data

collection

took

place

in

ten

Dutch

nursing

homes

-LRB-

N

-RRB-

The

proportion

of

residents

that

could

complete

each

scale

varied

The

Depression

List

could

be

administered

most

often

to

the

cognitively

most

impaired

group

-LRB-

Mini

Mental

State

Examination-scores

-RRB-

In

the

three

cognition

groups

with

MMSE-score

internal

consistency

of

the

Depression

List

Geriatric

Depression

Scale

and

Negative

Affect

Scale

was

adequate

in

all

three

groups

-LRB-

alpha

-RRB-

Intercorrelation

was

highest

for

the

Philadelphia

Geriatric

Center

Morale

Scale

the

Depression

List

and

the

Geriatric

Depression

Scale

-LRB-

rho

-RRB-

Nonetheless

self-report

scales

were

not

strongly

correlated

with

two

observational

scales

for

depression

especially

in

cognitively

severely

impaired

residents

-LRB-

rho

-RRB-

In

conclusion

it

may

not

be

possible

to

measure

overall

quality

of

life

through

self-report

and

possibly

also

through

observation

in

many

nursing

home

residents

Introduction

Over

the

past

decades

quality

of

life

has

become

a

focal

point

in

scientific

research

and

clinical

practice

Although

researchers

disagree

on

the

domains

that

make

up

quality

of

life

the

general

consensus

is

that

quality

of

life

measurement

should

focus

on

the

subjective

experience

of

the

individual

This

implies

that

the

individual

in

question

is

the

most

valid

source

of

information

-LSB-

-RSB-

However

nursing

home

residents

may

not

be

able

to

respond

to

self-report

measures

or

lose

this

ability

during

their

stay

f.i.

due

to

dementia

which

complicates

the

assessment

and

monitoring

of

a

resident

's

quality

of

life

across

time

-LSB-

-RSB-

Although

self-report

is

a

complex

process

of

introspection

and

evaluation

-LSB-

-RSB-

research

has

asserted

that

moderately

demented

patients

still

can

report

on

their

quality

of

life

even

when

they

have

poor

insight

into

and

awareness

of

their

dementia

-LSB-

-RSB-

According

to

Kane

et

al.

-LSB-

-RSB-

of

the

nursing

home

population

would

be

able

to

reliably

report

on

their

quality

of

life

It

would

therefore

be

helpful

to

know

which

scales

can

be

applied

to

nursing

home

residents

with

varying

degrees

of

cognitive

impairment

Most

scales

measure

separate

dimensions

of

quality

of

life

-LSB-

-RSB-

This

has

the

advantage

of

a

higher

responsiveness

to

change

than

a

measure

for

overall

quality

of

life

-LRB-

OQOL

-RRB-

However

OQOL

is

an

attractive

outcome

that

can

be

measured

as

a

single

subjective

result

of

weighing

unspecified

dimensions

that

are

considered

to

be

relevant

by

the

patient

The

administration

is

also

less

burdening

which

is

an

important

factor

in

a

very

frail

elderly

population

Therefore

several

researchers

-LRB-

also

-RRB-

use

a

single

overall

measure

-LSB-

e.g.

-RSB-

In

our

approach

to

quality

of

life

-LSB-

-RSB-

OQOL

is

represented

by

subjective

-LRB-

i.e.

psychological

-RRB-

well-being

Given

this

scales

for

subjective

-LRB-

psychological

-RRB-

well-being

can

be

used

as

OQOL

scales

Although

not

always

considered

as

the

central

outcome

psychological

well-being

is

an

important

dimension

of

quality

of

life

in

many

other

approaches

to

quality

of

life

in

the

elderly

-LSB-

-RSB-

It

encompasses

both

positive

and

negative

affect

and

life

satisfaction

-LRB-

i.e.

morale

and

contentment

-RRB-

-LSB-

-RSB-

but

most

often

a

selection

of

these

concepts

is

used

for

measurement

Instruments

for

psychological

well-being

that

are

used

in

the

elderly

are

for

instance

the

Philadelphia

Geriatric

Center

Morale

Scale

-LRB-

PGCMS

-RRB-

-LSB-

-RSB-

and

the

Bradburn

Affect

Balance

Scale

-LSB-

-RSB-

For

measuring

affect

in

the

elderly

the

Positive

and

Negative

Affect

Scales

-LSB-

-RSB-

and

the

observational

Philadelphia

Geriatric

Center

Positive

and

Negative

Affect

Scales

-LSB-

-RSB-

have

been

recommended

-LSB-

-RSB-

Both

positive

affect

and

negative

affect

are

important

dimensions

in

quality

of

life

scales

-LSB-

-RSB-

Sometimes

however

only

negative

scales

such

as

scales

for

depression

are

used

in

the

measurement

of

quality

of

life

-LSB-

-RSB-

As

the

absence

of

depression

does

not

automatically

imply

that

a

resident

is

happy

or

content

this

poses

the

question

of

whether

positive

and

negative

scales

do

indeed

measure

separate

constructs

and

thus

whether

or

not

a

negative

scale

can

be

used

as

a

single

scale

for

OQOL

In

this

paper

the

aim

is

to

investigate

the

usefulness

of

six

self-report

measurement

scales

for

OQOL

by

studying

whether

they

can

be

administered

reliably

and

validly

in

a

large

group

of

nursing

home

residents

and

whether

this

is

related

to

cognitive

impairment

We

hypothesized

that

if

all

scales

measure

OQOL

in

nursing

home

patients

validly

and

reliably

they

would

correlate

highly

within

all

cognition

groups

Moreover

the

scales

should

be

related

to

observational

scales

that

measure

OQOL

Methods

Data

were

collected

in

ten

nursing

homes

in

the

Netherlands

The

Medical

Ethics

Committee

of

the

VU

University

Medical

Center

had

approved

the

research

proposal

and

written

informed

consent

was

obtained

from

the

participants

or

their

legal

representative

Data

were

collected

on

a

maximum

sample

of

residents

over

a

period

of

months

per

nursing

home

with

an

equal

distribution

of

residents

with

mainly

physical

handicaps

-LRB-

in

so-called

somatic

units

-RRB-

and

mainly

dementia

syndromes

-LRB-

in

so-called

psychogeriatric

units

-RRB-

The

principal

investigator

-LRB-

DLG

a

trained

psychologist

-RRB-

administered

the

self-report

OQOL

scales

and

the

cognitive

test

-LRB-

see

later

-RRB-

while

the

nursing

staff

carried

out

the

observational

assessments

The

completeness

of

the

interview

data

depended

on

the

resident

's

cognitive

and

physical

abilities

and

willingness

to

answer

questions

The

scales

were

administered

in

random

order

The

administration

of

a

scale

was

terminated

when

a

resident

proved

to

be

unwilling

or

unable

to

respond

to

the

questions

that

were

asked

To

assure

the

validity

of

cross-sectional

comparisons

the

self-report

and

observational

scales

for

each

resident

were

both

assessed

within

the

same

period

Measurement

instruments

The

scales

that

were

selected

to

measure

OQOL

had

been

used

before

in

published

research

among

nursing

home

residents

or

frail

elderly

populations

A

distinction

was

made

between

scales

that

ask

about

OQOL

literally

scales

that

focus

on

positive

affect

negative

affect

or

life-satisfaction

and

scales

that

indicate

clinical

depression

Self-report

OQOL

scales

A

general

question

on

OQOL

-LRB-

GEN-QOLQ

-RRB-

was

asked

Overall

how

would

you

rate

the

quality

of

your

life

at

the

moment

This

is

a

modification

of

the

general

question

on

quality

of

life

that

is

part

of

Brod

and

co-workers

scale

for

quality

of

life

in

people

with

dementia

-LSB-

-RSB-

To

our

question

at

the

moment

was

added

because

a

pilot

study

showed

that

without

this

explicit

time-limit

the

residents

tended

to

evaluate

the

whole

of

their

past

life

The

response

scale

which

is

presented

in

the

form

of

a

card

consists

of

the

following

response

categories

bad

moderate

good

very

good

and

excellent

The

Philadelphia

Geriatric

Center

Morale

Scale

-LRB-

PGCMS

-RRB-

-LSB-

-RSB-

is

a

self-report

scale

that

has

been

developed

to

assess

elderly

people

in

institutions

and

has

regularly

been

used

as

an

outcome

measure

in

research

on

quality

of

life

and

well-being

in

the

elderly

-LSB-

e.g.

-RSB-

It

consists

of

dichotomous

items

measuring

life

satisfaction

and

the

scores

are

summed

with

a

high

score

indicating

high

quality

of

life

The

scale

has

been

found

to

be

reliable

valid

and

sensitive

-LSB-

-RSB-

and

internally

consistent

-LRB-

of

-RRB-

-LSB-

-RSB-

The

Positive

And

Negative

Affect

Scales

-LRB-

PANAS

-RRB-

-LSB-

-RSB-

were

also

used

The

Positive

Affect

Scale

-LRB-

PAS

-RRB-

consists

of

items

concerning

positive

feelings

such

as

enthusiasm

interest

and

determination

The

Negative

Affect

Scale

-LRB-

NAS

-RRB-

consists

of

items

concerning

negative

feelings

such

as

fear

sadness

anxiety

and

hostility

For

this

study

the

time

frame

today

was

chosen

and

instead

of

the

original

scale

a

response

scale

was

used

because

a

pilot

study

showed

that

very

few

residents

were

able

to

answer

the

scale

The

administration

was

visually

mediated

following

the

procedure

proposed

for

the

Depression

List

-LRB-

see

further

-RRB-

Summing

the

item-scores

yielded

two

separate

total

scores

ranging

from

-LRB-

no

positive/negative

affects

confirmed

-RRB-

to

-LRB-

all

positive/negative

affects

confirmed

-RRB-

The

PAS

and

the

NAS

were

found

to

be

suitable

for

use

in

the

elderly

-LSB-

-RSB-

Earlier

reported

internal

consistency

with

the

time-frame

of

today

yielded

a

Cronbach

's

alpha

of

for

the

PAS

and

for

the

NAS

in

the

general

population

-LSB-

-RSB-

The

Depression

List

-LRB-

DL

-RRB-

is

a

Dutch

self-report

screening

instrument

for

depression

especially

suitable

for

the

assessment

of

-LRB-

elderly

-RRB-

people

with

cognitive

impairment

-LSB-

-RSB-

It

consists

of

keywords

that

are

presented

on

cards

one

by

one

accompanied

by

a

simple

question

For

instance

a

card

with

down

printed

on

it

is

accompanied

by

the

question

do

you

feel

down

Sum-scores

range

from

-LRB-

no

depressive

complaints

-RRB-

to

-LRB-

many

depressive

complaints

-RRB-

In

psychometric

research

the

reported

internal

consistency

of

the

DL

was

in

a

group

of

visitors

to

a

psychogeriatric

day-care

clinic

-LSB-

-RSB-

The

Geriatric

Depression

Scale

-LRB-

GDS

-RRB-

is

a

self-report

screening

instrument

for

depression

in

the

elderly

that

is

of

known

reliability

and

validity

also

in

long-term

care

-LSB-

-RSB-

It

consists

of

dichotomous

questions

which

are

summed

into

total

scores

ranging

from

-LRB-

no

depressive

complaints

-RRB-

to

-LRB-

many

depressive

complaints

-RRB-

Other

scales

The

Mini

Mental

State

Examination

-LRB-

MMSE

-RRB-

is

a

test

for

cognition

and

has

scores

ranging

from

-LRB-

very

severe

cognitive

impairment

-RRB-

to

-LRB-

no

cognitive

impairment

-RRB-

It

is

widely

used

and

has

been

validated

also

in

long

term

care

populations

-LSB-

-RSB-

The

GIP-sad

behavior

-LSB-

-RSB-

is

a

sub-scale

of

the

Behavior

Observation

Scale

for

Geriatric

Inpatients

-LRB-

GIP

-RRB-

which

is

widely

used

in

nursing

homes

in

the

Netherlands

The

GIP-sad

behavior

-LRB-

GIP-S

-RRB-

measures

the

behavior

of

elderly

people

in

intramural

care

settings

that

expresses

sadness

unhappiness

and

anxiety

and

is

used

in

the

present

paper

as

a

scale

for

OQOL

Sum-scores

range

from

-LRB-

no

sad

behavior

-RRB-

to

-LRB-

frequent

sad

behavior

-RRB-

When

first

published

the

internal

consistency

-LRB-

Cronbach

's

alpha

-RRB-

of

the

scale

was

and

the

inter-rater

reliability

-LRB-

Pearson

's

r

-RRB-

was

-LSB-

-RSB-

In

a

validation

study

internal

consistency

was

found

to

be

and

the

average

inter-rater

reliability

of

the

items

-LRB-

Cohen

's

weighted

kappa

-RRB-

was

-LSB-

-RSB-

The

MDS

Depression

Rating

Scale

-LRB-

DRS

-RRB-

is

an

observational

scale

based

on

items

from

the

Minimal

Data

Set

of

the

Resident

Assessment

Instrument

-LSB-

-RSB-

which

can

be

used

to

screen

for

depression

-LSB-

-RSB-

The

DRS

consists

of

seven

MDS

items

that

are

summed

The

scores

range

from

-LRB-

no

depressive

behavior

-RRB-

to

-LRB-

frequent

depressive

behavior

-RRB-

The

internal

consistency

-LRB-

Cronbach

's

alpha

-RRB-

when

it

was

developed

was

in

the

derivation

sample

and

in

the

validation

sample

Its

sensitivity

against

a

psychiatric

diagnosis

of

depression

was

-LSB-

-RSB-

In

a

validity

study

the

internal

consistency

of

the

DRS

was

and

its

correlations

with

the

Geriatric

Depression

Scale

-LRB-

GDS

-RRB-

and

the

Hamilton

Depression

Rating

Scale

were

and

respectively

-LSB-

-RSB-

Analyses

In

order

to

determine

whether

cognitive

status

relates

to

the

psychometric

properties

of

the

scales

the

total

group

of

residents

was

divided

into

four

MMSE

score-groups

An

attempt

was

made

to

find

a

division

based

on

known

cut-off

points

that

also

resulted

in

equally

large

groups

The

traditional

MMSE

cut-off

point

indicating

cognitive

impairment

is

-LSB-

-RSB-

Among

the

reported

cut-off

points

for

severe

cognitive

impairment

are

and

-LSB-

-RSB-

and

known

cut-off

points

for

reliable

self-report

assessment

are

-LSB-

e.g.

-RSB-

and

-LSB-

e.g.

-RSB-

The

division

into

cognition

groups

was

carried

out

as

follows

a

MMSE

score

below

-LRB-

very

low

cognition

group

-RRB-

scores

from

to

-LRB-

low

cognition

group

-RRB-

scores

from

to

-LRB-

moderate

cognition

group

-RRB-

and

scores

of

or

higher

-LRB-

high

cognition

group

-RRB-

For

each

MMSE

score-group

the

number

of

residents

who

could

complete

each

scale

was

calculated

and

compared

with

the

number

of

residents

to

whom

it

was

offered

Cronbach

's

alphas

were

calculated

to

determine

the

internal

consistency

of

the

scales

and

were

compared

across

the

different

cognition

groups

Cronbach

's

alpha

is

considered

to

be

fairly

good

if

higher

than

but

should

not

be

higher

than

-LSB-

-RSB-

For

construct

validity

Spearman

coefficients

for

the

interrelationships

of

the

self-report

OQOL

scales

and

for

the

relationships

of

the

OQOL

scales

with

the

observational

scales

for

OQOL

were

calculated

and

compared

across

the

different

cognition

groups

Significant

correlation

coefficients

are

described

in

the

results

and

interpreted

as

follows

fair

correlation

substantial

correlation

and

strong

correlation

Results

Sample

description

The

overall

sample

consisted

of

residents

Their

average

age

was

-LRB-

SD

range

-RRB-

and

were

female

The

average

score

on

the

MMSE

-LRB-

N

-RRB-

was

-LRB-

SD

-RRB-

had

a

score

below

and

had

a

score

of

or

higher

The

internal

consistency

of

the

MMSE

in

this

sample

was

The

curves

of

the

NAS

and

the

DL

were

slightly

positively

skewed

The

scores

on

the

NAS

scales

were

found

to

be

quite

low

-LRB-

Table

descriptives

total

group

-RRB-

Table

and

practical

utility

of

self-report

overall

quality

of

life-scalesScales

-LRB-

max

range

-RRB-

Descriptives

total

groupAvailable

MMSE

scores

residents

who

could

complete

a

scale

per

MMSE

score

groupaMean

-LRB-

range

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

PGCMS

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

PAS

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

NegativeNAS

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

DL

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

GDS

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aEach

fraction

presents

the

number

of

residents

who

completed

the

scale

in

relation

to

the

total

number

of

residents

who

were

offered

the

scale

Because

the

scales

were

not

offered

to

all

participants

the

numbers

in

the

denominators

do

not

add

up

to

and

differ

for

each

scale

Due

to

practical

considerations

and

the

frailty

of

the

residents

not

all

scales

were

administered

to

all

residents

Therefore

the

number

of

completed

scales

varied

Proportion

of

completed

scales

Table

reports

that

in

the

high

cognition

group

-LRB-

MMSE

score

of

or

higher

-RRB-

all

six

scales

could

be

completed

by

of

the

residents

In

the

moderate

cognition

group

-LRB-

MMSE

score

between

and

-RRB-

all

scales

except

the

GEN-QOLQ

and

the

PGCMS

could

be

completed

by

of

the

residents

The

GEN-QOLQ

and

the

PGCMS

could

be

completed

by

and

in

this

group

respectively

In

the

low

cognitiongroup

-LRB-

MMSE

score

-RRB-

the

DL

still

could

be

completed

by

all

residents

-LRB-

-RRB-

the

PAS

and

the

NAS

by

the

GEN-QOLQ

by

and

the

PGCMS

and

the

GDS

by

In

the

very

low

cognition

group

-LRB-

MMSE

score

below

-RRB-

the

DL

could

still

be

completed

by

of

the

residents

but

only

or

less

could

complete

the

other

scales

The

GDS

was

not

completed

by

any

of

these

residents

and

the

PGCMS

only

by

Only

MMSE-groups

were

used

for

all

further

analyses

because

in

the

very

low

cognition

group

-LRB-

N

-RRB-

too

few

residents

could

complete

the

scales

Internal

consistency

The

GEN-QOLQ

consisted

of

one

question

so

internal

consistency

analysis

was

not

applicable

Table

shows

that

internal

consistency

of

the

DL

and

GDS

was

satisfactory

in

all

cognition

groups

that

of

the

NAS

was

also

acceptable

although

this

scale

was

somewhat

less

consistent

in

the

high

cognition

group

-LRB-

-RRB-

The

PGCMS

shows

good

consistency

except

in

the

moderate

cognition

group

-LRB-

-RRB-

The

PAS

is

the

least

reliable

scale

as

it

only

reaches

an

acceptable

alpha

in

the

moderate

cognition

group

Further

the

scales

showed

no

linear

trends

of

decreasing

internal

consistency

with

increasing

cognitive

impairment

but

there

were

some

variations

between

cognitive

groups

Table

consistency

of

self-report

overall

quality

of

life-scales

for

different

cognition

groupsTotal

groupHigh

cognition

MMSE

cognition

MMSE

cognition

MMSE

-LRB-

miic

-RRB-

bNcAlpha

-LRB-

miic

-RRB-

NAlpha

-LRB-

miic

-RRB-

NAlpha

-LRB-

miic

-RRB-

NPositivePGCMSd

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Cronbach

's

alpha

bMiic

mean

inter-item

correlationcThe

Ns

of

the

MMSE-groups

do

not

add

up

to

the

N

of

the

total

group

because

some

participants

-LRB-

N

of

N

-RRB-

did

not

have

an

MMSE-scoredAs

it

consists

of

one

question

no

alpha

coefficient

could

be

calculated

for

GEN-QOLQ

Construct

validity

Construct

validity

inter-relationship

Table

presents

the

Spearman

correlation

coefficients

for

the

self-report

OQOL

scales

in

the

three

cognition

groups

Each

correlation

coefficient

for

two

scales

pertains

to

all

residents

who

completed

both

scales

Therefore

the

group-sizes

differ

for

the

correlation

coefficients

Also

the

group

sizes

may

be

larger

than

in

Table

because

scale-scores

were

also

calculated

when

one

of

the

scale

's

items

was

missing

using

mean

substitution

Table

correlation

coefficients

between

self-report

overall

quality

of

life

scales

for

the

separate

MMSE

score-groupsGEN-QOLQPGCMSPASNASDLHCaMCLCHCMCLCHCMCLCHCMCLCHCMCLCPositivePGCMS

High

cognition

group

-LRB-

MMSE

score

-RRB-

MC

moderate

cognition

group

-LRB-

MMSE

score

-RRB-

LC

Low

cognition

group

-LRB-

MMSE

score

-RRB-

P

P

Table

shows

that

the

PGCMS

DL

and

GDS

had

the

strongest

intercorrelation

These

three

scales

correlated

significantly

-LRB-

P

-RRB-

in

all

cognition

groups

Also

the

NAS

was

substantially

correlated

with

the

GDS

and

the

DL

The

other

relationships

between

the

scales

varied

As

far

as

the

different

cognitive

groups

are

concerned

although

the

correlations

between

the

scales

were

mostly

lowest

in

the

low

cognition

group

no

clear

linear

trend

across

cognition

groups

was

visible

The

strength

of

the

relationships

between

the

positive

PGCMS

and

the

negative

NAS

DL

and

GDS

further

indicates

that

these

constructs

are

far

from

independent

as

often

has

been

found

Construct

validity

relationship

with

GIP-S

and

DRS

As

Table

shows

the

GIP-S

correlated

significantly

with

the

GEN-QOLQ

PGCMS

NAS

DL

and

GDS

but

only

in

the

moderate

cognition

groups

The

DRS

correlated

only

significantly

to

the

GEN-QOLQ

-LRB-

only

for

the

high

cognition

group

-RRB-

PGCMS

-LRB-

for

both

high

and

moderate

cognition

-RRB-

DL

-LRB-

for

moderate

cognition

-RRB-

and

GDS

-LRB-

for

both

high

and

moderate

cognition

-RRB-

of

the

self-report

scales

correlated

significantly

with

the

observational

scales

in

the

low

cognition

group

Remarkably

there

was

no

correlation

between

the

NAS

and

the

DRS.

The

correlation

coefficients

for

the

GIP-S

and

the

DRS

-LRB-

not

shown

in

Table

-RRB-

were

in

the

high

cognition

group

-LRB-

N

-RRB-

in

the

moderate

cognition

group

-LRB-

N

-RRB-

and

in

the

low

cognition

group

-LRB-

N

-RRB-

In

the

very

low

cognition

group

in

which

almost

no

self-report

scales

could

be

administered

the

correlation

between

these

two

observational

scales

was

-LRB-

N

-RRB-

Table

of

self-report

overall

quality

of

life-scales

with

observational

measures

for

overall

quality

of

life

for

the

separate

MMSE

score-groupsPositiveNegativeGEN-QOLQ

N

N

N

N

N

N

106HCaMCLCHCMCLCHCMCLCHCMCLCHCMCLCHCMCLCGIP-Srho

N

N

High

cognition

group

-LRB-

MMSE

score

-RRB-

MC

Moderate

cognition

group

-LRB-

MMSE

score

-RRB-

LC

Low

cognition

group

-LRB-

MMSE

score

-RRB-

P

P

Discussion

The

aim

of

this

paper

was

to

investigate

the

usefulness

of

six

self-report

scales

for

measuring

OQOL

in

nursing

home

residents

Hence

it

was

examined

what

percentage

of

residents

could

complete

each

scale

how

high

internal

consistency

and

construct

validity

of

the

scales

were

and

whether

these

results

were

associated

with

level

of

cognitive

impairment

It

appeared

that

of

all

the

scales

considered

here

the

DL

could

be

administered

to

the

most

residents

even

to

almost

half

-LRB-

-RRB-

of

the

residents

with

very

severe

cognitive

impairment

The

other

scales

could

only

be

administered

to

a

small

minority

of

this

group

However

in

the

higher

cognition

groups

all

scales

-LRB-

except

for

the

PGCMS

in

the

MMSE

group

-RRB-

could

be

administered

to

to

of

the

residents

This

percentage

is

higher

than

the

that

was

reported

by

Kane

et

al.

-LSB-

-RSB-

but

refers

to

shorter

scales

that

only

measure

OQOL

instead

of

various

dimensions

of

quality

of

life

In

addition

to

residents

being

able

to

complete

a

scale

the

resulting

psychometric

properties

of

the

scales

are

of

importance

It

appeared

that

all

scales

with

the

exception

of

the

PAS

and

to

a

lesser

extent

the

PGCMS

had

an

acceptable

internal

consistency

Although

the

alphas

varied

across

the

cognition

groups

there

was

no

linear

trend

of

decreasing

consistency

with

increasing

cognitive

impairment

With

regard

to

validity

the

PGCMS

DL

and

GDS

-LRB-

and

the

NAS

to

a

lesser

extent

-RRB-

were

strongly

interrelated

in

all

cognition

groups

although

the

correlations

in

the

low

cognition

group

overall

were

somewhat

lower

These

four

scales

also

had

the

strongest

relationships

with

the

observational

scales

for

OQOL

However

these

relationships

were

not

very

strong

Moreover

in

the

low

cognition

group

the

scales

were

not

related

to

the

observational

scales

This

suggests

that

level

of

cognitive

impairment

has

a

substantial

influence

on

the

validity

of

self-report

OQOL-scales

The

PAS

performed

worst

on

all

aspects

The

low

internal

consistency

in

the

high

cognition

group

could

be

explained

by

one

item

-LRB-

determined

-RRB-

When

it

was

omitted

Cronbach

's

alpha

increased

from

to

Furthermore

its

disappointing

characteristics

may

partly

be

explained

by

the

fact

that

the

PAS

measures

a

somewhat

different

construct

than

the

other

scales

Its

low

correlation

with

the

NAS

the

other

PANAS

scale

is

not

unexpected

Positive

and

negative

affect

are

considered

to

be

largely

independent

Considering

the

item

content

of

the

five

scales

six

affects

-LRB-

items

-RRB-

of

the

PAS

were

not

included

in

the

PGCMS

the

DL

or

the

GDS

-LRB-

i.e.

interested

exited

strong

proud

inspired

and

determined

-RRB-

whereas

only

three

affects

of

the

NAS

were

not

included

-LRB-

i.e.

guilty

hostile

and

shameful

-RRB-

The

PAS

therefore

must

be

considered

to

measure

a

different

construct

than

the

other

scales

which

also

explains

the

absence

of

a

correlation

with

the

GIP-sad

behavior

and

the

Depression

Rating

Scale

Although

conceptually

it

may

be

a

good

addition

to

the

measurement

of

OQOL

as

psychological

well-being

is

made

up

of

positive

affect

negative

affect

and

life

satisfaction

its

poor

psychometric

performance

make

it

unsuitable

in

its

present

form

In

contrast

the

other

PANAS

scale

the

NAS

had

quite

good

properties

although

the

mean

score

on

the

NAS

was

low

The

rating

of

affective

states

ideally

involves

a

consideration

of

intensity

duration

and

frequency

-LSB-

-RSB-

However

in

cognitively

impaired

residents

it

is

important

to

use

a

self-report

scale

that

is

as

simple

as

possible

which

may

lead

to

loss

of

information

and

therefore

a

loss

of

psychometric

quality

For

instance

the

dichotomized

response

scale

and

the

time-frame

of

today

that

was

used

for

the

PAS

and

the

NAS

may

have

resulted

in

less

discriminatory

and

lower

scores

but

increasing

the

response

categories

and

the

time-frame

would

threaten

its

reliability

We

therefore

suggest

further

research

into

the

optimal

time

frame

and

response

categories

of

the

NAS

Although

the

DL

and

the

GDS

have

been

developed

as

screening

instruments

for

depression

they

correlated

very

strongly

with

the

PGCMS

which

is

a

scale

for

life

satisfaction

Studying

the

item

content

of

the

scales

it

appeared

that

the

items

of

these

three

scales

have

many

similarities

The

items

of

the

DL

and

the

GDS

contain

positive

as

well

as

negative

affects

and

also

contentment

-LRB-

e.g.

satisfied

happy

and

hopeful

-RRB-

Remarkably

although

the

PGCMS

is

considered

to

be

a

positive

scale

it

has

more

items

that

contain

negative

affects

or

cognitions

-LRB-

out

of

-RRB-

than

the

GDS

-LRB-

out

of

-RRB-

and

especially

the

DL

-LRB-

out

of

-RRB-

Therefore

despite

the

fact

that

the

names

of

the

GDS

and

the

DL

suggest

a

negative

scale

they

both

contain

ample

positive

items

Likewise

the

PGCMS

can

not

be

considered

to

be

a

solely

positive

scale

So

with

adapted

scoring

methods

each

of

these

scales

could

be

used

as

a

single

measure

for

OQOL

covering

both

positive

and

negative

aspects

As

in

most

proxy

studies

-LSB-

-RSB-

in

the

present

study

low

correlation

was

found

between

self-report

and

proxy

assessment

in

low

cognition

groups

-LRB-

in

this

study

observational

scales

rated

by

the

nursing

staff

-RRB-

This

may

suggest

that

the

validity

of

self-report

scales

decreases

with

the

level

of

cognition

but

also

that

the

validity

of

observational

scales

is

lower

in

the

low

cognition

group

Indeed

the

correlation

between

the

two

observational

scales

in

this

study

was

lower

in

the

low

cognition

group

Nevertheless

the

relationships

between

the

self-report

and

observational

scales

were

also

not

strong

in

the

high

cognition

group

This

suggests

that

although

they

are

certainly

related

self-report

and

observational

scales

may

measure

a

different

construct

irrespective

of

the

cognitive

functioning

of

the

resident

The

fact

that

both

observational

scales

were

negative

may

have

complicated

matters

even

further

Additional

research

into

the

relationship

of

self-report

and

observational

scales

for

OQOL

as

well

as

proxy-report

measures

-LRB-

following

Edelman

et

al.

and

Sloane

et

al.

-LSB-

-RSB-

-RRB-

in

relation

to

cognitive

performance

is

therefore

necessary

This

research

should

use

positive

observational

scales

for

OQOL

for

instance

the

Philadelphia

Geriatric

Center

Positive

and

Negative

Affect

Scales

-LSB-

-RSB-

It

should

also

apply

a

shorter

maximum

time-interval

for

collecting

observational

data

than

the

four

week-period

used

in

this

study

since

this

may

have

resulted

in

an

underestimation

of

the

association

between

the

self-report

scales

on

the

one

hand

and

the

observational

scales

on

the

other

For

now

the

decision

as

to

whether

or

not

a

self-report

scale

can

still

be

administered

reliably

and

validly

in

a

cognitively

impaired

resident

could

best

be

made

for

individual

assessments

when

administering

a

quality

of

life-scale

The

research

on

quality

of

life

measurement

in

dementia

has

shown

that

one

can

use

screening

questions

incorporated

in

the

scale

and

thus

tailored

to

the

specific

cognitive

demands

of

the

scale

in

order

to

determine

whether

a

resident

is

cognitively

able

to

answer

the

questions

-LSB-

-RSB-

Nevertheless

even

if

a

resident

appears

to

be

able

to

understand

the

questions

it

is

not

certain

that

her

answers

are

a

true

reflection

of

her

inner

state

Therefore

further

research

should

focus

on

developing

guidelines

on

when

the

administration

of

a

scale

can

be

considered

as

reliable

and

valid

This

research

could

for

instance

study

the

possibility

of

examining

test-retest

reliability

by

repeating

questions

of

a

scale

throughout

the

assessment

Such

test-retest

reliability

in

the

assessment

of

cognitively

impaired

residents

is

an

important

indication

that

the

resident

has

understood

the

questions

and

that

she

really

communicates

her

true

subjective

state

In

addition

repeating

the

assessment

on

another

day

and

calculating

a

mean

score

for

the

two

assessments

can

result

in

a

more

stable

self-report

OQOL

score

In

conclusion

measuring

overall

quality

of

life

reliably

and

validly

through

self-report

may

not

be

possible

in

nursing

home

residents

with

at

least

moderate

cognitive

impairment

The

quality

of

observational

assessment

of

OQOL

may

also

be

lower

in

cognitively

impaired

residents

Before

drawing

definite

conclusions

about

the

usefulness

of

self-report

scales

it

is

necessary

to

study

their

reproducibility

Nevertheless

in

clinical

practice

using

self-report

scales

will

provide

interesting

information

on

the

experience

of

the

residents

and

is

therefore

in

itself

a

valuable

addition

to

observational

data

The

Depression

List

is

a

useful

scale

in

this

respect

especially

for

the

assessment

of

nursing

home

residents

with

mild

to

moderate

cognitive

impairment

O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

self-report outcome measures
long term care
age-related memory disorders