31 Staging Dementia - Navarra
31 Staging Dementia - Navarra
31 Staging Dementia - Navarra
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<strong>31</strong><br />
<strong>Staging</strong> <strong>Dementia</strong><br />
Barry Reisberg 1 , Imran A. Jamil 1 , Sharjeel Khan 1 , Isabel Monteiro 1 , Carol Torossian 1 , Steven Ferris 1 ,<br />
Marwan Sabbagh 2 , Serge Gauthier 3 , Stefanie Auer 4 , Melanie B. Shulman 1 , Alan Kluger 1 ,<br />
Emile Franssen 1 and Jerzy Wegiel 5<br />
1 Aging and <strong>Dementia</strong> Clinical Research Center, New York University Langone Medical Center,<br />
Center of Excellence on Brain Aging, New York, NY, USA<br />
2 Cleo Ruberts Center, Banner-Sun Health Research Institute, Sun City, AZ, USA<br />
3 McGill Center for Studies in Aging, Douglas Hospital, Montreal, Quebec, Canada<br />
4 MAS Alzheimerhilfe, Bad Ischl, Austria<br />
5 New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA<br />
INTRODUCTION AND OVERVIEW OF DEMENTIA<br />
STAGING<br />
<strong>Dementia</strong> is a progressive pathological process extending over<br />
a period of many years. Clinicians and scientists have long<br />
endeavoured to describe the nature of dementia progression. Such<br />
descriptions have generally been encompassed within two broad<br />
categories: global staging and more specific staging, sometimes<br />
referred to as axial or multi-axial staging. A comparison of the<br />
major current dementia staging systems with the most widely used<br />
mental status assessment in Alzheimer’s disease, the major cause of<br />
dementia, is shown in Figure <strong>31</strong>.1.<br />
This Figure illustrates some of the major potential advantages of<br />
staging. These advantages include: (i) staging can identify premorbid,<br />
but potentially manifest conditions which may be associated<br />
with the evolution of subsequent dementia, such as subjective cognitive<br />
impairment, a condition which is not differentiated with mental<br />
status or psychometric tests; (ii) staging can be very useful in identifying<br />
subtle predementia states, such as mild cognitive impairment<br />
(MCI), wherein mental status assessments and psychometric tests,<br />
while frequently altered, are generally within the normal range and,<br />
consequently, are not reliable markers 17–19 ; and (iii) staging can track<br />
the latter 50% of the potential time course of dementias such as<br />
Alzheimer’s disease (AD), when mental status assessments are virtually<br />
invariably at bottom (zero) scores 20 . Furthermore, apart from<br />
their utility in portions of dementia where mental status and psychometric<br />
assessments are out of range, or insensitive, there are<br />
clear data indicating that staging procedures can more accurately<br />
and sensitively identify the course of dementia in the portion of<br />
the condition which is conventionally charted with mental status<br />
assessments. This latter evidence comes from longitudinal investigation<br />
of the course of AD 9 , pharmacological treatment investigation<br />
of AD 21–23 , and study of independent psychometric assessments of<br />
AD 24 . For example, longitudinal study has demonstrated that the<br />
Functional Assessment <strong>Staging</strong> procedure (FAST) 5 and the Global<br />
Deterioration Scale (GDS) 3 accounted for more than twice the variance<br />
in the course of AD over a five-year mean interval, compared<br />
to the Mini-Mental State Examination (MMSE) 7,9 . When employed<br />
together, the GDS and the FAST staging procedures explained nearly<br />
three times the variance in the temporal course of AD compared to<br />
the MMSE (i.e. change in measure versus change in time), with<br />
the MMSE encompassing only 10% of temporal change variance<br />
and the GDS and FAST together encompassing 28% of the temporal<br />
change variance 9 . In pharmacological studies, staging procedures<br />
have frequently demonstrated sensitivity to effects of the interventions<br />
in pivotal studies where mental status assessment has not shown<br />
a significant effect. This superiority in the demonstration of pharmacological<br />
treatment efficacy for staging procedures over mental status<br />
assessment has been seen for both classes of currently approved pharmacotherapeutic<br />
agents; that is, for N -methyl-D-aspartate (NMDA)<br />
receptor antagonist treatment decreasing glutamate-induced excitotoxicity,<br />
and for cholinesterase inhibitor treatment enhancing cholinergic<br />
brain functioning. For example, a pivotal, multicentre trial<br />
associated with worldwide approvals of memantine treatment for<br />
AD found a robust statistically significant effect of the memantine,<br />
NMDA receptor antagonist treatment with the FAST staging<br />
procedure, but no significant effect was observed with the MMSE<br />
evaluation 21 . Similarly, in a pivotal study associated with worldwide<br />
approval of the cholinesterase inhibitor, rivastigmine, it was found<br />
that low dose treatment (1–4 mg/day) was associated with significant<br />
improvement on the GDS staging procedure, but not on the<br />
MMSE assessment 22 . Additionally, study of predominantly institutionalized<br />
persons with more advanced AD in the latter portion of the<br />
MMSE range (i.e. with MMSE scores of 10 or below), with specially<br />
designed psychometric procedures for advanced AD patients, have<br />
clearly shown that the FAST staging procedures can robustly track<br />
progressive change in these more advanced AD patients, in conjunction<br />
with special psychometric procedures, whereas the MMSE does<br />
not sensitively change in this more severe range 24 . Another potential<br />
advantage of staging procedures in comparison with mental status<br />
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<br />
© 2011 John Wiley & Sons, L td. ISBN: 978-0-470-74723-0
Normal adult<br />
Clinical diagnosis Subjective cognitive<br />
impairment<br />
(SCI)<br />
CDR stage a<br />
GDS & FAST stage a<br />
DIAGNOSIS AND ASSESSMENT 163<br />
Mild cognitive<br />
Impairment<br />
(MCI)<br />
0 0.5 1 2<br />
3<br />
1 2 3 4 5 6<br />
7<br />
FAST substage abcde a b c d e f<br />
Years b<br />
MMSE c<br />
Psychometric<br />
tests<br />
Approximately<br />
30 to 50<br />
years<br />
Normal adult<br />
Mild<br />
AD<br />
29 29 29 25 19 14<br />
Normal adult range<br />
Subjective and clinically manifest cognitive impairment<br />
Clinically manifest cognitive impairment<br />
Approximately 15 years<br />
0<br />
Questionable<br />
impairment<br />
Mod<br />
AD<br />
5<br />
Impaired<br />
<strong>Dementia</strong><br />
Severe dement. phase<br />
0<br />
Severe AD<br />
7 9 10.5 13 19<br />
Uniform bottom<br />
scores d<br />
and usual<br />
stage of death<br />
a Stage range comparisons shown between the CDR and GDS/FAST stages are based upon published functioning and self-care<br />
descriptors.<br />
b Numerical values represent time in years.<br />
For GDS and FAST stage 1, the temporal values are subsequent to the onset of adult life.<br />
For GDS and FAST stage 2, the temporal value is prior to onset of mild cognitive impairment symptoms.<br />
For GDS and FAST stage 3 and above, the values are subsequent to the onset of mild cognitive impairment symptoms.<br />
In all cases, the temporal values refer to the evolution of Alzheimer’s disease pathology.<br />
All temporal estimates are based upon the GDS and FAST scales and were initially published based upon clinical observations in<br />
Reisberg, Geriatrics 1986; 41(4): 30–468 . These estimates have been supported by subsequent clinical and pathological cross-sectional<br />
and longitudinal investigations (e.g. Reisberg et al., Int Psychogeriatr 1996; 8: 291–<strong>31</strong>19 ; Bobinski et al.,<br />
<strong>Dementia</strong> 1995; 6: 205–1010 ; Bobinski et al., J Neuropathol Exp Neurol 1997; 56: 414–2011 ;<br />
Kluger et al., J Geriatr Psychiatry Neurol 1999; 12: 168–7912 ; Prichep et al., Neurobiol Aging, 2006; 27: 471–8113 ; Reisberg and Gauthier,<br />
Int Psychogeriatr 2008; 20: 1–1614 ; Wegiel et al., Acta Neuropathol 2008; 116: 391–40715 ; Reisberg et al., Alzheimers Dement<br />
2010; 6(1): 11–2416 ).<br />
The spacing in the figure is approximately proportional to the temporal duration of the respective stages and substages, with the exception<br />
of GDS and FAST stage 1, for which the broken lines signify an abbreviated temporal duration spacing for this normal adult condition<br />
which lasts approximately 30 to 50 years.<br />
c MMSE scores are approximate mean values from prior published studies.<br />
d For typical adult psychometric tests.<br />
Mod<br />
sev AD<br />
Figure <strong>31</strong>.1 Typical time course of normal brain ageing; mild cognitive impairment associated with Alzheimer’s disease and the dementia<br />
of Alzheimer’s disease. AD, Alzheimer’s disease; CDR, Clinical <strong>Dementia</strong> Rating 1,2 ; GDS, Global Deterioration Scale 3,4 ; FAST, Functional<br />
Assessment <strong>Staging</strong> 5,6 ; MMSE, Mini-Mental State Examination 7 ; Mod AD, moderate Alzheimer’s disease; Mod sev AD, moderately severe<br />
Alzheimer’s disease. Copyright © 2007, 2009 Barry Reisberg, MD. All rights reserved
164 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRY<br />
or psychometric assessment of AD and other dementias, is in identifying<br />
the management concomitants of severity assessments 25,26 .<br />
<strong>Staging</strong> procedures have also been successfully applied postmortem<br />
to retrospectively assess the diagnoses (i.e. AD or other non-AD<br />
dementia) of a diverse assortment of dementia-related cases available<br />
for ‘brain banking’, but on which no antemortem clinical data were<br />
available 27 . Similarly, postmortem retrospective staging procedures<br />
have been successful in establishing remarkably robust clinicopathological<br />
correlations in longitudinally studied AD cohorts 10,11,15,20 .<br />
GLOBAL STAGING<br />
Efforts to globally stage progressive dementia can be traced back<br />
at least to the early nineteenth century when the English psychiatrist,<br />
James Prichard, described four stages in the progression of<br />
dementia: ‘(1) impairment of recent memory, (2) loss of reason, (3)<br />
incomprehension, (4) loss of instinctive action’ 28,29 . More recently,<br />
the American Psychiatric Association’s 30 Diagnostic and Statistical<br />
Manual of Mental Disorders, 3rd edition (DSM-III) recognized three<br />
broad stages in its definition of primary degenerative dementia 30 .<br />
Subsequently, in 1982, two more detailed global descriptions of the<br />
progression of dementia were published. One of these, the Clinical<br />
<strong>Dementia</strong> Rating (CDR) scale 1 , describes five broad stages from<br />
normality to severe dementia. The other, the Global Deterioration<br />
Scale (GDS) 3 , identifies seven clinically recognizable stages from<br />
normality to most severe dementia of the Alzheimer type. A recently<br />
published abridged version of the GDS is shown in Table <strong>31</strong>.1 <strong>31</strong> .<br />
Complete versions of the CDR and the GDS scales can be found<br />
in the literature (e.g. for the original CDR, references 1,32 and for the<br />
CDR ‘current version’, reference 2 ; for the GDS, reference 3 ,andfor<br />
the tabular format of the GDS, reference 4 ). These two global staging<br />
instruments, the GDS and the CDR, are generally compatible except<br />
that the GDS is more detailed and specific and identifies two stages<br />
which the CDR staging does not.<br />
One of these stages identified by the GDS staging procedure but<br />
not by the CDR is a stage in which subjective complaints of cognitive<br />
deficit occur in the absence of clinically identifiable symptoms<br />
Table <strong>31</strong>.1 Abridged global deterioration scale<br />
(GDS stage 2). These subjective complaints are now recognized as<br />
occurring very commonly in older persons (e.g. 33–35 ). Although this<br />
stage of subjective complaints continues to be identified only by<br />
the GDS staging system, studies have indicated that persons with<br />
these complaints are at increased risk for subsequent overt dementia<br />
(e.g. 12,16,36–38 ). A distinct diagnostic terminology, namely, ‘subjective<br />
cognitive impairment’ (SCI), has recently been suggested for<br />
otherwise healthy older persons with these symptoms who are free<br />
of overtly manifest symptoms of mild cognitive impairment (MCI)<br />
or dementia 14,39 . A recent study, which is apparently the first to systematically<br />
examine the prognosis of GDS stage 2, SCI persons, in<br />
comparison with persons with no cognitive impairment (NCI, GDS<br />
stage 1), from the perspective of the subsequent development of MCI<br />
or dementia, has indicated the true morbidity associated with this SCI<br />
condition. Over a mean seven-year follow-up, the risk of subsequent<br />
decline to MCI or dementia was 4.5-times greater in persons with<br />
SCI (GDS stage 2) than in persons who are free of these subjective<br />
complaints, after controlling for differences in age and other demographic<br />
variables, as well as follow-up time 16 . Physiological differences<br />
between otherwise healthy older persons with these subjective<br />
complaints of cognitive impairment and similarly aged persons without<br />
these symptoms (i.e. between GDS stage 2 and GDS stage 1<br />
subjects) have now been reported for brain metabolism and cortisol<br />
levels 40,41 . Longitudinal studies are also presently confirming 13,14 a<br />
previously estimated 15-year duration 8 for this GDS stage 2 condition,<br />
identifying subjective impairment only, in the evolution of brain<br />
ageing and AD pathology.<br />
The GDS staging measure and associated assessments from the<br />
GDS staging system also identify a stage, GDS stage 3, for which the<br />
terminology mild cognitive impairment (MCI) was originally coined<br />
in 1988 42 . This GDS stage 3 is described, in part, as a stage in which:<br />
(i) the ‘earliest clear-cut deficits’ become manifest; (ii) ‘objective evidence<br />
of memory deficit is obtained only with an intensive interview’,<br />
and (iii) there is ‘decreased performance in demanding employment<br />
and social settings’. Many of the early observations with respect to<br />
the nature of MCI were made using this GDS stage 3 definition (see 17<br />
for a review), and the GDS 3 definition of MCI remains compatible<br />
Stage 1: NCI. No subjective memory deficit (no cognitive impairment); no problems with activities of daily living.<br />
Stage 2: SCI. Subjective cognitive impairment (subjective memory and/or other cognitive complaints): observations, sometimes<br />
accompanied by complaints, of being forgetful, such as of difficulties with recall of names, and/or of misplacing objects.<br />
Stage 3: MCI. Earliest subtle deficits (mild cognitive impairment): difficulties often noted at work; may have become lost; may<br />
have misplaced a valuable object.<br />
Stage 4: Mild dementia. Clear deficits on clinical examination (moderate cognitive impairment): decreased knowledge of<br />
personal and/or current events; often difficulties with finances or shopping or meal preparation or travel.<br />
Stage 5: Moderate dementia. Can no longer survive independently in the community without some assistance (moderately<br />
severe cognitive impairment): difficulty with recall of some important personal details (e.g. address, names of one or more<br />
important schools attended); may require cueing for activities for daily living.<br />
Stage 6: Moderately severe dementia. Largely unable to verbalize recent events in their life (severe cognitive impairment): may<br />
forget name of spouse; incontinence develops as this stage progresses; requires increasing assistance with activities for daily<br />
living such as dressing and showering. Increased behavioural problems (e.g. agitation) or other personality problems are<br />
common.<br />
Stage 7: Severe dementia. Few intelligible words or no verbal abilities (very severe cognitive impairment): the ability to walk is<br />
lost as this stage evolves. Later, basic capacities such as the ability to sit up independently, to smile, and to move and/or to<br />
hold up the head independently are progressively lost.<br />
Copyright © 1983, 2008, 2009 Barry Reisberg, MD. All rights reserved.<br />
2009 abridged version. Original abridged version published in Canadian Medical Association Journal 2008; 179(12): 1281. Modified from Reisberg B, Ferris SH, de<br />
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<br />
by Winblad et al. in 2004 19 . The CDR staging methodology identifies<br />
a CDR 0.5 stage originally termed ‘questionable dementia’, which is<br />
somewhat broader in scope than the MCI entity, and which encompasses<br />
some of early (mild) dementia, as well as the MCI clinical<br />
timeframe.<br />
At the other end of the pathological spectrum, the CDR does not<br />
identify any stage beyond that in which dementia patients ‘require<br />
much help with personal care’ and are ‘often incontinent’. In contrast,<br />
the GDS identifies a final seventh GDS stage in which patients are<br />
already incontinent and over the course of which language and motor<br />
capacities are progressively lost. Importantly, the CDR does not stage<br />
or substage the latter portion of the dementia of AD, representing<br />
nine or more years of potential life and continuing decline for these<br />
patients (see Figure <strong>31</strong>.1). This absence of attention to the nature of<br />
severe dementia clinical changes in the CDR staging methodology<br />
may add to the neglect of persons with more advanced dementia<br />
and, in particular, the dementia of Alzheimer’s disease. In marked<br />
contrast with the CDR, the GDS identifies two stages (GDS stages<br />
6 and 7), corresponding to the CDR 3 stage range. Additionally, the<br />
other elements of the GDS staging system, described below, chart this<br />
latter portion of the dementia of AD in detail. For example, the FAST<br />
scale (described below) identifies eight substages corresponding to<br />
the CDR stage 3, ‘severe dementia’ range.<br />
In addition to the range differences discussed above and differing<br />
staging numbers, the CDR scale and the GDS staging scale<br />
also have different procedures for scoring. The original CDR versions<br />
used a ‘sum of boxes’ procedure, with means of the sum of<br />
boxes in six CDR assessment categories, i.e. (1) Memory, (2) Orientation,<br />
(3) Judgement and Problem Solving, (4) Community Affairs,<br />
(5) Home and Hobbies, and (6) Personal Care. However, current<br />
scoring procedures for the CDR are much more complex and more<br />
weighted towards the memory category. The GDS staging procedure<br />
simply requires the choice of the most appropriate global stage, based<br />
upon cognition and functioning. GDS staging descriptors acknowledge<br />
common emotional concomitants of the stages; however these<br />
are not employed in the stage selection. The comparisons shown in<br />
Figure <strong>31</strong>.1 between the CDR and the GDS/FAST staging categories<br />
and other assessment procedures are based upon the CDR functioning<br />
and self-care descriptions.<br />
In summary, with respect to range, the GDS staging and associated<br />
measures from the GDS <strong>Staging</strong> System, are much more detailed at<br />
both ends of the pathological spectrum of brain ageing and progressive<br />
dementia than the CDR staging. As discussed, the GDS staging<br />
identifies an SCI stage prior to the development of mild cognitive<br />
impairment, which the CDR staging does not refer to. Also, the GDS<br />
staging procedures are more rigorous in the definition of MCI and<br />
the separation of MCI from early dementia. In the severe end of the<br />
dementia spectrum, the GDS staging and the associated GDS <strong>Staging</strong><br />
System, described in greater detail in the next section, are much<br />
more detailed than the CDR.<br />
<strong>Staging</strong> procedures have been shown to be valid and reliable methods<br />
for assessing the magnitude of pathology in AD and related<br />
dementing conditions. This validity and reliability is illustrated in<br />
this brief review for the GDS, the most detailed and explicit staging<br />
procedure.<br />
The validity of the GDS has been demonstrated in several ways.<br />
Cross-sectional studies have confirmed the consistency of the ordinal<br />
sequence and the optimal weighting of the hierarchically sequenced<br />
items embodied in the GDS stages in ageing and progressive<br />
Alzheimer’s disease (AD) 42–45 . Thus, the specific impairments<br />
DIAGNOSIS AND ASSESSMENT 165<br />
characteristic of each stage almost always follow the impairments<br />
described for the previous stage. Also, the grouping of impairment<br />
characteristics within stages appears to be optimal.<br />
For example, naturalistic study has supported the identification of<br />
staging phenomena, largely identical to the GDS stages, by independent<br />
layperson observers. In this study 44 , a 30-item questionnaire<br />
derived from the GDS was completed by a relative or caregiver for<br />
each of 115 patients with varying degrees of dementia. Principal<br />
components analysis was used to combine the items into a single<br />
composite scale that more reliably represents distances between the<br />
30 clinical manifestations along the continuum of cognitive decline.<br />
In the study it was found that ‘the scale scores for the clinical manifestations<br />
were observed to cluster into relatively discrete groups,<br />
suggesting naturally occurring stages or phases. Objective cluster<br />
analysis methods further confirmed the presence of distinct transitions<br />
along the cognitive decline continuum.’ It was concluded that<br />
the ‘utility of empirically derived scale values in staging the course<br />
of primary degenerative dementia is suggested.’<br />
The relationship between the GDS stages and mental status<br />
assessments, other dementia assessments, scores on cognitive<br />
tests and other objective tests and in vivo assessments of brain<br />
change in ageing and progressive dementia have been studied in<br />
considerable detail 3,42 . These studies have indicated significant<br />
correlations between all of these measures of dementia severity and<br />
the GDS stages. However, the strongest relationships have been<br />
observed between comprehensive dementia assessments such as<br />
the Mini-Mental State Examination (MMSE) 7 and the progression<br />
of dementia on the GDS 42 . The GDS also correlates well with<br />
independent physical markers of AD progression such as changes in<br />
neurological reflexes 46 . Thus the construct validity of the GDS has<br />
been well substantiated.<br />
At least six separate studies have examined the reliability of the<br />
GDS 47–52 . Reliability coefficients have ranged from 0.82 to 0.97 in<br />
these studies using disparate procedures in diverse settings. These<br />
studies have indicated that the GDS is at least as reliable as any<br />
other instruments upon which clinicians rely, such as the MMSE. In<br />
a reliability study in a nursing home setting 51 , the GDS was found<br />
to be somewhat more reliable than the MMSE. Importantly, GDS<br />
staging has also been shown to be a reliable procedure when assessed<br />
using a telephone format 52 .<br />
Global staging scales such as the GDS have certain important<br />
advantages in dementia assessment. First and foremost, these scales<br />
are strongly anchored to the clinical symptoms, behaviour and functional<br />
changes in progressive degenerative dementia, and particularly<br />
those of Alzheimer’s disease. Consequently, they discourage<br />
misdiagnosis. Unlike many mental status and other dementia test<br />
instruments, global stages are relatively stable over time and relatively<br />
resistant to practice effects. Equally importantly, global staging<br />
instruments are minimally influenced by educational background and<br />
socioeconomic status, whereas mental status and similar assessments<br />
are strongly influenced by such factors. Also, as previously noted,<br />
global staging, and in particular the GDS, covers the entire range<br />
of pathology in central nervous system (CNS) ageing and progressive<br />
dementia, whereas, for example, mental status assessments and<br />
most psychometric tests entirely fail to distinguish GDS stages 1<br />
and 2 (i.e. NCI and SCI). Occasionally, patients may display GDS<br />
stage 3 symptomatology (MCI) and still score a perfect 30 on the<br />
MMSE. Uncommonly, dementia patients may display GDS stage 4<br />
symptomatology (mild dementia), and still score a perfect 30 on the<br />
MMSE. Much more commonly, patients may display the clear-cut<br />
dementia symptomatology characteristic of GDS stage 4 and achieve
166 PRINCIPLES AND PRACTICE OF GERIATRIC PSYCHIATRY<br />
MMSE scores which are near perfect or within the so-called ‘normal’<br />
range. At the other end of the pathological spectrum, most patients<br />
at GDS stage 6 (moderately severe dementia) achieve only bottom<br />
scores on traditional psychometric tests. Over the entire course of<br />
the GDS 7 (severe dementia) stage, most patients attain only zero<br />
(bottom) scores on the MMSE. The GDS, however, describes a final<br />
seventh stage, over the course of which patients may survive for<br />
many years.<br />
AXIAL AND MULTI-AXIAL STAGING<br />
The observation that the progression of dementia pathology is accompanied<br />
by progressive changes in more specifically defined processes,<br />
termed ‘axes’ has resulted in efforts to stage dementia in terms of<br />
those processes. Generally, axial staging has attempted to exploit<br />
progressive changes in cognition or functioning, although attempts<br />
have also been made to hierarchically stage progressive mood and<br />
behavioural changes, progressive motoric changes and progressive<br />
neurological changes, as well as other observable concomitants of<br />
dementia. These efforts can be traced back more than 40 years to the<br />
work of de Ajuriaguerra and associates 53–55 : Swiss investigators who<br />
were strongly influenced by Piaget’s investigations of the stages of<br />
normal infant and childhood development. More recently, Cole and<br />
co-workers in Canada employed this approach in their Hierarchic<br />
<strong>Dementia</strong> Scale 56–58 . A similar approach was pursued, apparently<br />
independently, by Gottfries and associates in Sweden 59 .<br />
The CDR staging has a ‘sum of boxes’ approach which employs<br />
a hierarchical, multi-axial-like procedure 60 , or, more recently, a<br />
modified, multi-axial-like procedure 2 . Based upon the seven-stage<br />
GDS, Reisberg and associates also described axial and multi-axial<br />
concomitants of progressive dementia 61,62 in a measure termed the<br />
Brief Cognitive Rating Scale (BCRS). Each of the BCRS axes has<br />
been enumerated to be optimally concordant with the corresponding<br />
GDS stages. Ultimately, the functional component of these BCRS<br />
axes resulted in the most detailed hierarchical staging of progressive<br />
dementia proposed to date, a 16-stage and substage measure of<br />
progressive functional change. This latter assessment is termed<br />
Functional Assessment <strong>Staging</strong> or FAST 5 (Table <strong>31</strong>.2).<br />
Like the BCRS axes, the FAST has been enumerated to be optimally<br />
concordant, in dementia of the Alzheimer type, with the corresponding<br />
GDS stages, discussed above. The FAST can be used<br />
as an independent staging measure of the magnitude of dementia<br />
pathology, or as part of the GDS <strong>Staging</strong> System 45 . Advantages of<br />
the FAST staging procedure include the following: (i) the FAST<br />
is capable of describing the entire course of brain-ageing associated,<br />
cognition-based functional changes and subsequent dementia<br />
of the Alzheimer type, ordinally (i.e. hierarchically), in unprecedented<br />
detail; (ii) the scale can assist in differentiating dementia of<br />
the Alzheimer type from other dementia processes 8,65,66 ; (iii) the<br />
scale can assist in identifying premature and potentially remediable<br />
functional changes in AD patients (e.g. premature loss of ambulation<br />
due, for example, to the side effects of medication) 8,65,66 ;(iv)<br />
the scale permits the retrospective as well as prospective examination<br />
of the temporal course of AD 10,11 ; and (v) the scale is the<br />
only current measure which permits the detailed staging of severe<br />
AD 20,23,24,43 . A strong relationship between this FAST procedure and<br />
comprehensive cognitive assessments such as the MMSE has long<br />
been noted 64,67 . However, because the MMSE and other cognitive<br />
modalities bottom out prior to the final five to eight FAST substages,<br />
complete concurrent validation and examination of the FAST had to<br />
await the development of cognitive measures useful in most severe<br />
dementia. Such measures were developed towards the end of the<br />
twentieth century and do, in fact, evidence strong relationships with<br />
the final FAST stages 24 . Subsequent work showed approximately<br />
equally strong relationships between this latter portion of the FAST<br />
and ostensibly cognition-independent neurological reflex changes 46 ,<br />
as well as hippocampal neuropathological changes in volume 10 , cell<br />
number 11 and the percentage of remaining hippocampal neurons with<br />
neurofibrillary changes 11 , with the advance of AD as per the FAST<br />
stages and substages (reviewed in 20 ). Also, the second layer of the<br />
entrohinal cortex is believed to be a very early site of AD pathology.<br />
In this layer, a very robust relationship, across the FAST severity<br />
spectrum from FAST stage 3 to 7f, with the decrement in neuronal<br />
numbers has recently been reported (r = 0.9) 15 . The correlations<br />
between the advance of AD as measured with the FAST in the latter<br />
portion of the course of AD, generally after the MMSE bottom<br />
(zero) point, and cognitive, neurological reflex and neuropathological<br />
hippocampal measures are generally approximately 0.8–0.9. These<br />
diverse relationships are comparable to the correlation between the<br />
FAST and the MMSE in the MMSE-sensitive portion of the FAST<br />
staging assessment. Because of these properties and others, the FAST<br />
has proven to be of widespread utility. For example, in the United<br />
States, the FAST staging procedure has been utilized as the Medicare<br />
mandated ‘gold standard’ for hospice admission for more than<br />
a decade 68 . Importantly, because of the sensitivity of the FAST staging<br />
procedure to the course of AD, not only over the final seventh<br />
stage when the MMSE is zero, but also over the course of FAST<br />
stage 6, when patients still score on measures such as the MMSE,<br />
the FAST measure has shown a significant effect on the course of<br />
AD in a pivotal multicentre drug trial, associated with worldwide<br />
approvals for memantine as the first medication for advanced AD,<br />
whereas the MMSE was not sensitive to change in this study 21 .At<br />
the present time, the FAST has been used as an efficacy and/or severity<br />
assessment in all pivotal trials associated with United States and<br />
European Union approvals of medications for advanced AD (for a<br />
review, see 23 ).<br />
Apart from the utility of the FAST staging, other elements of<br />
the multi-axial BCRS staging procedures have also proven useful in<br />
AD assessment. On the BCRS, Axis I assesses concentration; Axis<br />
II, recent memory; Axis III, remote memory; Axis IV, orientation;<br />
and Axis V, functioning. Axis V of the BCRS was developed and<br />
expanded in the process of the creation of the FAST staging procedure.<br />
All of these elements of the BCRS, including the FAST, have<br />
been utilized as part of the syncretic NYU CIBIC-Plus assessment<br />
measure 69 . As part of the NYU CIBIC-Plus, these measures have<br />
been used as primary outcome measures in pivotal trials associated<br />
with regulatory body (e.g. FDA) approvals of two of the three medications<br />
currently approved and marketed for the treatment of AD<br />
in the United States (i.e. rivastigmine and memantine) (for a review,<br />
see 23 ). At the other end of the brain-ageing and AD continuum, the<br />
BCRS Axes I to V have been found to add significantly to the GDS<br />
global assessment in predicting the risk of decline and the time to<br />
decline to MCI or dementia in ostensibly normal subjects with NCI<br />
or SCI (GDS stages 1 and 2) 16 .<br />
SUMMARY<br />
Behaviourally based brain-ageing and progressive dementia staging<br />
procedures can be useful and, frequently, superior to other assessment<br />
modalities in identifying potential treatments for AD and related
DIAGNOSIS AND ASSESSMENT 167<br />
Table <strong>31</strong>.2 Functional Assessment <strong>Staging</strong> (FAST) and time course of functional loss in normal brain ageing and<br />
Alzheimer’s disease<br />
FAST Clinical characteristics Clinical diagnosis Estimated Mean<br />
stage duration in AD a MMSE b<br />
1 No decrement Normal adult 29–30<br />
2 Subjective deficit in word finding or<br />
recalling location of objects<br />
Subjective cognitive impairment 15 years 29<br />
3 Deficits noted in demanding employment<br />
settings<br />
Mild cognitive impairment 7 years 24–27<br />
4 Requires assistance in complex tasks, e.g.<br />
handling finances, planning dinner party<br />
Mild AD 2 years 19–20<br />
5 Requires assistance in choosing proper<br />
attire<br />
Moderate AD 18 months 15<br />
6a Requires assistance in dressing Moderately severe AD 5 months 9<br />
b Requires assistance in bathing properly 5 months 8<br />
c Requires assistance with mechanics of<br />
toileting (such as flushing, wiping)<br />
5 months 5<br />
d Urinary incontinence 4 months 3<br />
e Faecal incontinence 10 months 1<br />
7a Speech ability limited to about a<br />
half-dozen words<br />
Severe AD 12 months 0<br />
b Intelligible vocabulary limited to a single<br />
word<br />
18 months 0<br />
c Ambulatory ability lost 12 months 0<br />
d Ability to sit up lost 12 months 0<br />
e Ability to smile lost 18 months 0<br />
f Ability to hold up or move head<br />
independently lost<br />
12 months or longer<br />
Adapted from Reisberg, 1986 8 . Copyright © 1984 by Barry Reisberg, MD.<br />
a In subjects without other complicating illnesses who survive and progress to the subsequent deterioration stage 9–16 .<br />
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<br />
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<br />
education). The influence of these educational levels on the mean MMSE scores should be given consideration.<br />
dementias 70–72 , as well as in assessing the course and the management<br />
needs of the dementia patient, and also in the diagnosis<br />
and differential diagnosis of dementing disorders. In providing an<br />
overview of the course of dementias such as AD, from the initial to<br />
final clinical symptoms, staging is uniquely useful. <strong>Staging</strong> is also<br />
singularly useful in assessment at various specific points in the evolution<br />
of dementing processes. Very importantly, staging can uniquely<br />
relate to management needs and the general management import of<br />
dementing processes.<br />
ACKNOWLEDGEMENT<br />
This work was supported in part by US DHHS grants AG03051 and<br />
AG08051 from the National Institute on Aging of the US National<br />
Institutes of Health; by grants 90AZ2791, 90AM2552 and 90AR2160<br />
from the US Department of Health and Human Services Administration<br />
on Aging; by grant NCRRM01 RR00096 from the General<br />
Clinical Research Center Program and by Clinical and Translational<br />
Science Institute grant 1UL1RR029893 from the National Center for<br />
Disease Research Resources of the US National Institutes of Health;<br />
by the Zachary and Elizabeth M. Fisher Center for Alzheimer’s<br />
Research Foundation; by a grant from Mr. William Silberstein; by<br />
the Leonard Litwin Fund for Alzheimer’s Disease Research; by the<br />
Woodbourne Foundation; and by the Hagedorn Fund.<br />
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