31 Staging Dementia - Navarra

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31
Staging Dementia
Barry Reisberg 1 , Imran A. Jamil 1 , Sharjeel Khan 1 , Isabel Monteiro 1 , Carol Torossian 1 , Steven Ferris 1 ,
Marwan Sabbagh 2 , Serge Gauthier 3 , Stefanie Auer 4 , Melanie B. Shulman 1 , Alan Kluger 1 ,
Emile Franssen 1 and Jerzy Wegiel 5
1 Aging and Dementia Clinical Research Center, New York University Langone Medical Center,
Center of Excellence on Brain Aging, New York, NY, USA
2 Cleo Ruberts Center, Banner-Sun Health Research Institute, Sun City, AZ, USA
3 McGill Center for Studies in Aging, Douglas Hospital, Montreal, Quebec, Canada
4 MAS Alzheimerhilfe, Bad Ischl, Austria
5 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA
INTRODUCTION AND OVERVIEW OF DEMENTIA
STAGING
Dementia is a progressive pathological process extending over
a period of many years. Clinicians and scientists have long
endeavoured to describe the nature of dementia progression. Such
descriptions have generally been encompassed within two broad
categories: global staging and more specific staging, sometimes
referred to as axial or multi-axial staging. A comparison of the
major current dementia staging systems with the most widely used
mental status assessment in Alzheimer’s disease, the major cause of
dementia, is shown in Figure 31.1.
This Figure illustrates some of the major potential advantages of
staging. These advantages include: (i) staging can identify premorbid,
but potentially manifest conditions which may be associated
with the evolution of subsequent dementia, such as subjective cognitive
impairment, a condition which is not differentiated with mental
status or psychometric tests; (ii) staging can be very useful in identifying
subtle predementia states, such as mild cognitive impairment
(MCI), wherein mental status assessments and psychometric tests,
while frequently altered, are generally within the normal range and,
consequently, are not reliable markers 17–19 ; and (iii) staging can track
the latter 50% of the potential time course of dementias such as
Alzheimer’s disease (AD), when mental status assessments are virtually
invariably at bottom (zero) scores 20 . Furthermore, apart from
their utility in portions of dementia where mental status and psychometric
assessments are out of range, or insensitive, there are
clear data indicating that staging procedures can more accurately
and sensitively identify the course of dementia in the portion of
the condition which is conventionally charted with mental status
assessments. This latter evidence comes from longitudinal investigation
of the course of AD 9 , pharmacological treatment investigation
of AD 21–23 , and study of independent psychometric assessments of
AD 24 . For example, longitudinal study has demonstrated that the
Functional Assessment Staging procedure (FAST) 5 and the Global
Deterioration Scale (GDS) 3 accounted for more than twice the variance
in the course of AD over a five-year mean interval, compared
to the Mini-Mental State Examination (MMSE) 7,9 . When employed
together, the GDS and the FAST staging procedures explained nearly
three times the variance in the temporal course of AD compared to
the MMSE (i.e. change in measure versus change in time), with
the MMSE encompassing only 10% of temporal change variance
and the GDS and FAST together encompassing 28% of the temporal
change variance 9 . In pharmacological studies, staging procedures
have frequently demonstrated sensitivity to effects of the interventions
in pivotal studies where mental status assessment has not shown
a significant effect. This superiority in the demonstration of pharmacological
treatment efficacy for staging procedures over mental status
assessment has been seen for both classes of currently approved pharmacotherapeutic
agents; that is, for N -methyl-D-aspartate (NMDA)
receptor antagonist treatment decreasing glutamate-induced excitotoxicity,
and for cholinesterase inhibitor treatment enhancing cholinergic
brain functioning. For example, a pivotal, multicentre trial
associated with worldwide approvals of memantine treatment for
AD found a robust statistically significant effect of the memantine,
NMDA receptor antagonist treatment with the FAST staging
procedure, but no significant effect was observed with the MMSE
evaluation 21 . Similarly, in a pivotal study associated with worldwide
approval of the cholinesterase inhibitor, rivastigmine, it was found
that low dose treatment (1–4 mg/day) was associated with significant
improvement on the GDS staging procedure, but not on the
MMSE assessment 22 . Additionally, study of predominantly institutionalized
persons with more advanced AD in the latter portion of the
MMSE range (i.e. with MMSE scores of 10 or below), with specially
designed psychometric procedures for advanced AD patients, have
clearly shown that the FAST staging procedures can robustly track
progressive change in these more advanced AD patients, in conjunction
with special psychometric procedures, whereas the MMSE does
not sensitively change in this more severe range 24 . Another potential
advantage of staging procedures in comparison with mental status
P r inciples and P r actice o f G er iatr ic P s ychiatr y, Third Edition E dited by M ohammed T . A bou-Saleh, Cornelius K atona and A nand Kumar
© 2011 John Wiley & Sons, L td. ISBN: 978-0-470-74723-0

Normal adult
Clinical diagnosis Subjective cognitive
impairment
(SCI)
CDR stage a
GDS & FAST stage a
DIAGNOSIS AND ASSESSMENT 163
Mild cognitive
Impairment
(MCI)
0 0.5 1 2
3
1 2 3 4 5 6
7
FAST substage abcde a b c d e f
Years b
MMSE c
Psychometric
tests
Approximately
30 to 50
years
Normal adult
Mild
AD
29 29 29 25 19 14
Normal adult range
Subjective and clinically manifest cognitive impairment
Clinically manifest cognitive impairment
Approximately 15 years
0
Questionable
impairment
Mod
AD
5
Impaired
Dementia
Severe dement. phase
0
Severe AD
7 9 10.5 13 19
Uniform bottom
scores d
and usual
stage of death
a Stage range comparisons shown between the CDR and GDS/FAST stages are based upon published functioning and self-care
descriptors.
b Numerical values represent time in years.
For GDS and FAST stage 1, the temporal values are subsequent to the onset of adult life.
For GDS and FAST stage 2, the temporal value is prior to onset of mild cognitive impairment symptoms.
For GDS and FAST stage 3 and above, the values are subsequent to the onset of mild cognitive impairment symptoms.
In all cases, the temporal values refer to the evolution of Alzheimer’s disease pathology.
All temporal estimates are based upon the GDS and FAST scales and were initially published based upon clinical observations in
Reisberg, Geriatrics 1986; 41(4): 30–468 . These estimates have been supported by subsequent clinical and pathological cross-sectional
and longitudinal investigations (e.g. Reisberg et al., Int Psychogeriatr 1996; 8: 291–3119 ; Bobinski et al.,
Dementia 1995; 6: 205–1010 ; Bobinski et al., J Neuropathol Exp Neurol 1997; 56: 414–2011 ;
Kluger et al., J Geriatr Psychiatry Neurol 1999; 12: 168–7912 ; Prichep et al., Neurobiol Aging, 2006; 27: 471–8113 ; Reisberg and Gauthier,
Int Psychogeriatr 2008; 20: 1–1614 ; Wegiel et al., Acta Neuropathol 2008; 116: 391–40715 ; Reisberg et al., Alzheimers Dement
2010; 6(1): 11–2416 ).
The spacing in the figure is approximately proportional to the temporal duration of the respective stages and substages, with the exception
of GDS and FAST stage 1, for which the broken lines signify an abbreviated temporal duration spacing for this normal adult condition
which lasts approximately 30 to 50 years.
c MMSE scores are approximate mean values from prior published studies.
d For typical adult psychometric tests.
Mod
sev AD
Figure 31.1 Typical time course of normal brain ageing; mild cognitive impairment associated with Alzheimer’s disease and the dementia
of Alzheimer’s disease. AD, Alzheimer’s disease; CDR, Clinical Dementia Rating 1,2 ; GDS, Global Deterioration Scale 3,4 ; FAST, Functional
Assessment Staging 5,6 ; MMSE, Mini-Mental State Examination 7 ; Mod AD, moderate Alzheimer’s disease; Mod sev AD, moderately severe
Alzheimer’s disease. Copyright © 2007, 2009 Barry Reisberg, MD. All rights reserved

164 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRY
or psychometric assessment of AD and other dementias, is in identifying
the management concomitants of severity assessments 25,26 .
Staging procedures have also been successfully applied postmortem
to retrospectively assess the diagnoses (i.e. AD or other non-AD
dementia) of a diverse assortment of dementia-related cases available
for ‘brain banking’, but on which no antemortem clinical data were
available 27 . Similarly, postmortem retrospective staging procedures
have been successful in establishing remarkably robust clinicopathological
correlations in longitudinally studied AD cohorts 10,11,15,20 .
GLOBAL STAGING
Efforts to globally stage progressive dementia can be traced back
at least to the early nineteenth century when the English psychiatrist,
James Prichard, described four stages in the progression of
dementia: ‘(1) impairment of recent memory, (2) loss of reason, (3)
incomprehension, (4) loss of instinctive action’ 28,29 . More recently,
the American Psychiatric Association’s 30 Diagnostic and Statistical
Manual of Mental Disorders, 3rd edition (DSM-III) recognized three
broad stages in its definition of primary degenerative dementia 30 .
Subsequently, in 1982, two more detailed global descriptions of the
progression of dementia were published. One of these, the Clinical
Dementia Rating (CDR) scale 1 , describes five broad stages from
normality to severe dementia. The other, the Global Deterioration
Scale (GDS) 3 , identifies seven clinically recognizable stages from
normality to most severe dementia of the Alzheimer type. A recently
published abridged version of the GDS is shown in Table 31.1 31 .
Complete versions of the CDR and the GDS scales can be found
in the literature (e.g. for the original CDR, references 1,32 and for the
CDR ‘current version’, reference 2 ; for the GDS, reference 3 ,andfor
the tabular format of the GDS, reference 4 ). These two global staging
instruments, the GDS and the CDR, are generally compatible except
that the GDS is more detailed and specific and identifies two stages
which the CDR staging does not.
One of these stages identified by the GDS staging procedure but
not by the CDR is a stage in which subjective complaints of cognitive
deficit occur in the absence of clinically identifiable symptoms
Table 31.1 Abridged global deterioration scale
(GDS stage 2). These subjective complaints are now recognized as
occurring very commonly in older persons (e.g. 33–35 ). Although this
stage of subjective complaints continues to be identified only by
the GDS staging system, studies have indicated that persons with
these complaints are at increased risk for subsequent overt dementia
(e.g. 12,16,36–38 ). A distinct diagnostic terminology, namely, ‘subjective
cognitive impairment’ (SCI), has recently been suggested for
otherwise healthy older persons with these symptoms who are free
of overtly manifest symptoms of mild cognitive impairment (MCI)
or dementia 14,39 . A recent study, which is apparently the first to systematically
examine the prognosis of GDS stage 2, SCI persons, in
comparison with persons with no cognitive impairment (NCI, GDS
stage 1), from the perspective of the subsequent development of MCI
or dementia, has indicated the true morbidity associated with this SCI
condition. Over a mean seven-year follow-up, the risk of subsequent
decline to MCI or dementia was 4.5-times greater in persons with
SCI (GDS stage 2) than in persons who are free of these subjective
complaints, after controlling for differences in age and other demographic
variables, as well as follow-up time 16 . Physiological differences
between otherwise healthy older persons with these subjective
complaints of cognitive impairment and similarly aged persons without
these symptoms (i.e. between GDS stage 2 and GDS stage 1
subjects) have now been reported for brain metabolism and cortisol
levels 40,41 . Longitudinal studies are also presently confirming 13,14 a
previously estimated 15-year duration 8 for this GDS stage 2 condition,
identifying subjective impairment only, in the evolution of brain
ageing and AD pathology.
The GDS staging measure and associated assessments from the
GDS staging system also identify a stage, GDS stage 3, for which the
terminology mild cognitive impairment (MCI) was originally coined
in 1988 42 . This GDS stage 3 is described, in part, as a stage in which:
(i) the ‘earliest clear-cut deficits’ become manifest; (ii) ‘objective evidence
of memory deficit is obtained only with an intensive interview’,
and (iii) there is ‘decreased performance in demanding employment
and social settings’. Many of the early observations with respect to
the nature of MCI were made using this GDS stage 3 definition (see 17
for a review), and the GDS 3 definition of MCI remains compatible
Stage 1: NCI. No subjective memory deficit (no cognitive impairment); no problems with activities of daily living.
Stage 2: SCI. Subjective cognitive impairment (subjective memory and/or other cognitive complaints): observations, sometimes
accompanied by complaints, of being forgetful, such as of difficulties with recall of names, and/or of misplacing objects.
Stage 3: MCI. Earliest subtle deficits (mild cognitive impairment): difficulties often noted at work; may have become lost; may
have misplaced a valuable object.
Stage 4: Mild dementia. Clear deficits on clinical examination (moderate cognitive impairment): decreased knowledge of
personal and/or current events; often difficulties with finances or shopping or meal preparation or travel.
Stage 5: Moderate dementia. Can no longer survive independently in the community without some assistance (moderately
severe cognitive impairment): difficulty with recall of some important personal details (e.g. address, names of one or more
important schools attended); may require cueing for activities for daily living.
Stage 6: Moderately severe dementia. Largely unable to verbalize recent events in their life (severe cognitive impairment): may
forget name of spouse; incontinence develops as this stage progresses; requires increasing assistance with activities for daily
living such as dressing and showering. Increased behavioural problems (e.g. agitation) or other personality problems are
common.
Stage 7: Severe dementia. Few intelligible words or no verbal abilities (very severe cognitive impairment): the ability to walk is
lost as this stage evolves. Later, basic capacities such as the ability to sit up independently, to smile, and to move and/or to
hold up the head independently are progressively lost.
Copyright © 1983, 2008, 2009 Barry Reisberg, MD. All rights reserved.
2009 abridged version. Original abridged version published in Canadian Medical Association Journal 2008; 179(12): 1281. Modified from Reisberg B, Ferris SH, de
Leon MJ et al. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatry 1982; 139: 1136–9.

with the current international consensus definition of MCI, published
by Winblad et al. in 2004 19 . The CDR staging methodology identifies
a CDR 0.5 stage originally termed ‘questionable dementia’, which is
somewhat broader in scope than the MCI entity, and which encompasses
some of early (mild) dementia, as well as the MCI clinical
timeframe.
At the other end of the pathological spectrum, the CDR does not
identify any stage beyond that in which dementia patients ‘require
much help with personal care’ and are ‘often incontinent’. In contrast,
the GDS identifies a final seventh GDS stage in which patients are
already incontinent and over the course of which language and motor
capacities are progressively lost. Importantly, the CDR does not stage
or substage the latter portion of the dementia of AD, representing
nine or more years of potential life and continuing decline for these
patients (see Figure 31.1). This absence of attention to the nature of
severe dementia clinical changes in the CDR staging methodology
may add to the neglect of persons with more advanced dementia
and, in particular, the dementia of Alzheimer’s disease. In marked
contrast with the CDR, the GDS identifies two stages (GDS stages
6 and 7), corresponding to the CDR 3 stage range. Additionally, the
other elements of the GDS staging system, described below, chart this
latter portion of the dementia of AD in detail. For example, the FAST
scale (described below) identifies eight substages corresponding to
the CDR stage 3, ‘severe dementia’ range.
In addition to the range differences discussed above and differing
staging numbers, the CDR scale and the GDS staging scale
also have different procedures for scoring. The original CDR versions
used a ‘sum of boxes’ procedure, with means of the sum of
boxes in six CDR assessment categories, i.e. (1) Memory, (2) Orientation,
(3) Judgement and Problem Solving, (4) Community Affairs,
(5) Home and Hobbies, and (6) Personal Care. However, current
scoring procedures for the CDR are much more complex and more
weighted towards the memory category. The GDS staging procedure
simply requires the choice of the most appropriate global stage, based
upon cognition and functioning. GDS staging descriptors acknowledge
common emotional concomitants of the stages; however these
are not employed in the stage selection. The comparisons shown in
Figure 31.1 between the CDR and the GDS/FAST staging categories
and other assessment procedures are based upon the CDR functioning
and self-care descriptions.
In summary, with respect to range, the GDS staging and associated
measures from the GDS Staging System, are much more detailed at
both ends of the pathological spectrum of brain ageing and progressive
dementia than the CDR staging. As discussed, the GDS staging
identifies an SCI stage prior to the development of mild cognitive
impairment, which the CDR staging does not refer to. Also, the GDS
staging procedures are more rigorous in the definition of MCI and
the separation of MCI from early dementia. In the severe end of the
dementia spectrum, the GDS staging and the associated GDS Staging
System, described in greater detail in the next section, are much
more detailed than the CDR.
Staging procedures have been shown to be valid and reliable methods
for assessing the magnitude of pathology in AD and related
dementing conditions. This validity and reliability is illustrated in
this brief review for the GDS, the most detailed and explicit staging
procedure.
The validity of the GDS has been demonstrated in several ways.
Cross-sectional studies have confirmed the consistency of the ordinal
sequence and the optimal weighting of the hierarchically sequenced
items embodied in the GDS stages in ageing and progressive
Alzheimer’s disease (AD) 42–45 . Thus, the specific impairments
DIAGNOSIS AND ASSESSMENT 165
characteristic of each stage almost always follow the impairments
described for the previous stage. Also, the grouping of impairment
characteristics within stages appears to be optimal.
For example, naturalistic study has supported the identification of
staging phenomena, largely identical to the GDS stages, by independent
layperson observers. In this study 44 , a 30-item questionnaire
derived from the GDS was completed by a relative or caregiver for
each of 115 patients with varying degrees of dementia. Principal
components analysis was used to combine the items into a single
composite scale that more reliably represents distances between the
30 clinical manifestations along the continuum of cognitive decline.
In the study it was found that ‘the scale scores for the clinical manifestations
were observed to cluster into relatively discrete groups,
suggesting naturally occurring stages or phases. Objective cluster
analysis methods further confirmed the presence of distinct transitions
along the cognitive decline continuum.’ It was concluded that
the ‘utility of empirically derived scale values in staging the course
of primary degenerative dementia is suggested.’
The relationship between the GDS stages and mental status
assessments, other dementia assessments, scores on cognitive
tests and other objective tests and in vivo assessments of brain
change in ageing and progressive dementia have been studied in
considerable detail 3,42 . These studies have indicated significant
correlations between all of these measures of dementia severity and
the GDS stages. However, the strongest relationships have been
observed between comprehensive dementia assessments such as
the Mini-Mental State Examination (MMSE) 7 and the progression
of dementia on the GDS 42 . The GDS also correlates well with
independent physical markers of AD progression such as changes in
neurological reflexes 46 . Thus the construct validity of the GDS has
been well substantiated.
At least six separate studies have examined the reliability of the
GDS 47–52 . Reliability coefficients have ranged from 0.82 to 0.97 in
these studies using disparate procedures in diverse settings. These
studies have indicated that the GDS is at least as reliable as any
other instruments upon which clinicians rely, such as the MMSE. In
a reliability study in a nursing home setting 51 , the GDS was found
to be somewhat more reliable than the MMSE. Importantly, GDS
staging has also been shown to be a reliable procedure when assessed
using a telephone format 52 .
Global staging scales such as the GDS have certain important
advantages in dementia assessment. First and foremost, these scales
are strongly anchored to the clinical symptoms, behaviour and functional
changes in progressive degenerative dementia, and particularly
those of Alzheimer’s disease. Consequently, they discourage
misdiagnosis. Unlike many mental status and other dementia test
instruments, global stages are relatively stable over time and relatively
resistant to practice effects. Equally importantly, global staging
instruments are minimally influenced by educational background and
socioeconomic status, whereas mental status and similar assessments
are strongly influenced by such factors. Also, as previously noted,
global staging, and in particular the GDS, covers the entire range
of pathology in central nervous system (CNS) ageing and progressive
dementia, whereas, for example, mental status assessments and
most psychometric tests entirely fail to distinguish GDS stages 1
and 2 (i.e. NCI and SCI). Occasionally, patients may display GDS
stage 3 symptomatology (MCI) and still score a perfect 30 on the
MMSE. Uncommonly, dementia patients may display GDS stage 4
symptomatology (mild dementia), and still score a perfect 30 on the
MMSE. Much more commonly, patients may display the clear-cut
dementia symptomatology characteristic of GDS stage 4 and achieve

166 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRY
MMSE scores which are near perfect or within the so-called ‘normal’
range. At the other end of the pathological spectrum, most patients
at GDS stage 6 (moderately severe dementia) achieve only bottom
scores on traditional psychometric tests. Over the entire course of
the GDS 7 (severe dementia) stage, most patients attain only zero
(bottom) scores on the MMSE. The GDS, however, describes a final
seventh stage, over the course of which patients may survive for
many years.
AXIAL AND MULTI-AXIAL STAGING
The observation that the progression of dementia pathology is accompanied
by progressive changes in more specifically defined processes,
termed ‘axes’ has resulted in efforts to stage dementia in terms of
those processes. Generally, axial staging has attempted to exploit
progressive changes in cognition or functioning, although attempts
have also been made to hierarchically stage progressive mood and
behavioural changes, progressive motoric changes and progressive
neurological changes, as well as other observable concomitants of
dementia. These efforts can be traced back more than 40 years to the
work of de Ajuriaguerra and associates 53–55 : Swiss investigators who
were strongly influenced by Piaget’s investigations of the stages of
normal infant and childhood development. More recently, Cole and
co-workers in Canada employed this approach in their Hierarchic
Dementia Scale 56–58 . A similar approach was pursued, apparently
independently, by Gottfries and associates in Sweden 59 .
The CDR staging has a ‘sum of boxes’ approach which employs
a hierarchical, multi-axial-like procedure 60 , or, more recently, a
modified, multi-axial-like procedure 2 . Based upon the seven-stage
GDS, Reisberg and associates also described axial and multi-axial
concomitants of progressive dementia 61,62 in a measure termed the
Brief Cognitive Rating Scale (BCRS). Each of the BCRS axes has
been enumerated to be optimally concordant with the corresponding
GDS stages. Ultimately, the functional component of these BCRS
axes resulted in the most detailed hierarchical staging of progressive
dementia proposed to date, a 16-stage and substage measure of
progressive functional change. This latter assessment is termed
Functional Assessment Staging or FAST 5 (Table 31.2).
Like the BCRS axes, the FAST has been enumerated to be optimally
concordant, in dementia of the Alzheimer type, with the corresponding
GDS stages, discussed above. The FAST can be used
as an independent staging measure of the magnitude of dementia
pathology, or as part of the GDS Staging System 45 . Advantages of
the FAST staging procedure include the following: (i) the FAST
is capable of describing the entire course of brain-ageing associated,
cognition-based functional changes and subsequent dementia
of the Alzheimer type, ordinally (i.e. hierarchically), in unprecedented
detail; (ii) the scale can assist in differentiating dementia of
the Alzheimer type from other dementia processes 8,65,66 ; (iii) the
scale can assist in identifying premature and potentially remediable
functional changes in AD patients (e.g. premature loss of ambulation
due, for example, to the side effects of medication) 8,65,66 ;(iv)
the scale permits the retrospective as well as prospective examination
of the temporal course of AD 10,11 ; and (v) the scale is the
only current measure which permits the detailed staging of severe
AD 20,23,24,43 . A strong relationship between this FAST procedure and
comprehensive cognitive assessments such as the MMSE has long
been noted 64,67 . However, because the MMSE and other cognitive
modalities bottom out prior to the final five to eight FAST substages,
complete concurrent validation and examination of the FAST had to
await the development of cognitive measures useful in most severe
dementia. Such measures were developed towards the end of the
twentieth century and do, in fact, evidence strong relationships with
the final FAST stages 24 . Subsequent work showed approximately
equally strong relationships between this latter portion of the FAST
and ostensibly cognition-independent neurological reflex changes 46 ,
as well as hippocampal neuropathological changes in volume 10 , cell
number 11 and the percentage of remaining hippocampal neurons with
neurofibrillary changes 11 , with the advance of AD as per the FAST
stages and substages (reviewed in 20 ). Also, the second layer of the
entrohinal cortex is believed to be a very early site of AD pathology.
In this layer, a very robust relationship, across the FAST severity
spectrum from FAST stage 3 to 7f, with the decrement in neuronal
numbers has recently been reported (r = 0.9) 15 . The correlations
between the advance of AD as measured with the FAST in the latter
portion of the course of AD, generally after the MMSE bottom
(zero) point, and cognitive, neurological reflex and neuropathological
hippocampal measures are generally approximately 0.8–0.9. These
diverse relationships are comparable to the correlation between the
FAST and the MMSE in the MMSE-sensitive portion of the FAST
staging assessment. Because of these properties and others, the FAST
has proven to be of widespread utility. For example, in the United
States, the FAST staging procedure has been utilized as the Medicare
mandated ‘gold standard’ for hospice admission for more than
a decade 68 . Importantly, because of the sensitivity of the FAST staging
procedure to the course of AD, not only over the final seventh
stage when the MMSE is zero, but also over the course of FAST
stage 6, when patients still score on measures such as the MMSE,
the FAST measure has shown a significant effect on the course of
AD in a pivotal multicentre drug trial, associated with worldwide
approvals for memantine as the first medication for advanced AD,
whereas the MMSE was not sensitive to change in this study 21 .At
the present time, the FAST has been used as an efficacy and/or severity
assessment in all pivotal trials associated with United States and
European Union approvals of medications for advanced AD (for a
review, see 23 ).
Apart from the utility of the FAST staging, other elements of
the multi-axial BCRS staging procedures have also proven useful in
AD assessment. On the BCRS, Axis I assesses concentration; Axis
II, recent memory; Axis III, remote memory; Axis IV, orientation;
and Axis V, functioning. Axis V of the BCRS was developed and
expanded in the process of the creation of the FAST staging procedure.
All of these elements of the BCRS, including the FAST, have
been utilized as part of the syncretic NYU CIBIC-Plus assessment
measure 69 . As part of the NYU CIBIC-Plus, these measures have
been used as primary outcome measures in pivotal trials associated
with regulatory body (e.g. FDA) approvals of two of the three medications
currently approved and marketed for the treatment of AD
in the United States (i.e. rivastigmine and memantine) (for a review,
see 23 ). At the other end of the brain-ageing and AD continuum, the
BCRS Axes I to V have been found to add significantly to the GDS
global assessment in predicting the risk of decline and the time to
decline to MCI or dementia in ostensibly normal subjects with NCI
or SCI (GDS stages 1 and 2) 16 .
SUMMARY
Behaviourally based brain-ageing and progressive dementia staging
procedures can be useful and, frequently, superior to other assessment
modalities in identifying potential treatments for AD and related

DIAGNOSIS AND ASSESSMENT 167
Table 31.2 Functional Assessment Staging (FAST) and time course of functional loss in normal brain ageing and
Alzheimer’s disease
FAST Clinical characteristics Clinical diagnosis Estimated Mean
stage duration in AD a MMSE b
1 No decrement Normal adult 29–30
2 Subjective deficit in word finding or
recalling location of objects
Subjective cognitive impairment 15 years 29
3 Deficits noted in demanding employment
settings
Mild cognitive impairment 7 years 24–27
4 Requires assistance in complex tasks, e.g.
handling finances, planning dinner party
Mild AD 2 years 19–20
5 Requires assistance in choosing proper
attire
Moderate AD 18 months 15
6a Requires assistance in dressing Moderately severe AD 5 months 9
b Requires assistance in bathing properly 5 months 8
c Requires assistance with mechanics of
toileting (such as flushing, wiping)
5 months 5
d Urinary incontinence 4 months 3
e Faecal incontinence 10 months 1
7a Speech ability limited to about a
half-dozen words
Severe AD 12 months 0
b Intelligible vocabulary limited to a single
word
18 months 0
c Ambulatory ability lost 12 months 0
d Ability to sit up lost 12 months 0
e Ability to smile lost 18 months 0
f Ability to hold up or move head
independently lost
12 months or longer
Adapted from Reisberg, 1986 8 . Copyright © 1984 by Barry Reisberg, MD.
a In subjects without other complicating illnesses who survive and progress to the subsequent deterioration stage 9–16 .
b MMSE = Mini-Mental State Examination score (Folstein et al., 1975 7 ). Estimates based in part on published data summarized in Reisberg et al., 1989 63
and in Reisberg et al., 1992 64 . It should be noted that the educational level of the subjects in these studies is high (mean ∼15.5 years ±∼3 years, of formal
education). The influence of these educational levels on the mean MMSE scores should be given consideration.
dementias 70–72 , as well as in assessing the course and the management
needs of the dementia patient, and also in the diagnosis
and differential diagnosis of dementing disorders. In providing an
overview of the course of dementias such as AD, from the initial to
final clinical symptoms, staging is uniquely useful. Staging is also
singularly useful in assessment at various specific points in the evolution
of dementing processes. Very importantly, staging can uniquely
relate to management needs and the general management import of
dementing processes.
ACKNOWLEDGEMENT
This work was supported in part by US DHHS grants AG03051 and
AG08051 from the National Institute on Aging of the US National
Institutes of Health; by grants 90AZ2791, 90AM2552 and 90AR2160
from the US Department of Health and Human Services Administration
on Aging; by grant NCRRM01 RR00096 from the General
Clinical Research Center Program and by Clinical and Translational
Science Institute grant 1UL1RR029893 from the National Center for
Disease Research Resources of the US National Institutes of Health;
by the Zachary and Elizabeth M. Fisher Center for Alzheimer’s
Research Foundation; by a grant from Mr. William Silberstein; by
the Leonard Litwin Fund for Alzheimer’s Disease Research; by the
Woodbourne Foundation; and by the Hagedorn Fund.
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