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Alzheimers & Dementia 7 (2011) 253256

Editorial

Revised criteria for diagnosis of Alzheimers disease: National Institute


on Aging-Alzheimers Association diagnostic guidelines
for Alzheimers disease
The publication of revised criteria/guidelines for the diagno- Dx-AD criteria and offer recommendations for further
sis of Alzheimers disease (Dx-AD) in the current issue of action in the future concerning this work-in-progress.
Alzheimers & Dementia is a momentous milestone in the One of the questions concerning this revision iswhy there
prolonged history of efforts to characterize the distinct was a 27 years hiatus between the publication of the original
clinical-pathological features of a complex syndromeAlz- criteria and current version? Perhaps the next reiterations of
heimers disease (AD). The amendments to the current these criteria will occur at regular and shorter intervals. The
criteria recommended by the National Institute on Aging issue of a long lag time between re-evaluation/revision of
(NIA)-Alzheimers Association workgroups on diagnostic Dx-AD criteria is a serious matter for future progress in the
guidelines for Alzheimers disease represent significant prog- field; however, this concern needs to be moderated in the con-
ress in that endeavor by adding important new features that text of early struggles to advance the field. Although the study
would enhance the precision and accuracy of differential diag- of dementia has a 100-year history, systematic efforts to ad-
nosis of this syndrome. These revisions promise to have a pro- dress the array of scientific and clinical challenges to differen-
found impact on the pace and direction of future research as tial diagnosis of AD syndrome is a relatively recent
well as the global effort to find a cure. Our field owes a great phenomenon. Thus, several hurdles had to be overcome before
debt of gratitude to the members of the three workgroups, as the 1984 NINCDS-ADRDA criteria as well as during the inter-
well as to the NIA and the Alzheimers Association, for their vening period between 1984 and 2011 (e.g., the lack of vali-
leadership in crafting the first significant revision of the dated assessment tools, the necessary infrastructure for
NINCDS-ADRDA (National Institute of Neurological and systematic clinical/longitudinal studies).
Communicative Disorders and Stroke and the Alzheimers Dis- Historically, one of the early core issues for the field of
ease and Related Disorders Association) criteria [1] of 1984. dementia was the question of whether AD changes are sim-
Much of what the NIA-Alzheimers Association work- ply an accentuation of normal senescence. Even today, this
groups are recommending is a redefinition of AD to include problem remains to be a critical challenge. The landmark in-
3 stages: 1) a dementia stage for which the original vestigations by Blessed et al [2] began to address this issue in
NINCDS/ADRDA and the revised National Institute on late 1960s and set the stage for the subsequent efforts to dis-
Aging/Alzheimers Association criteria apply; 2) a mild cog- tinguish brain changes owing to pathology from those asso-
nitive impairment (MCI) stage where there are core criteria ciated with healthy aging.
for MCI but only guidelines of how to relate MCI to AD after In the United States, the trend for integrating clinical and
further research and validation of biomarkers; and 3) a preclin- biological studies of dementia (i.e., clinico-pathological cor-
ical stage where there are no criteria for diagnosis but, instead, relations) started to take shape a decade later in parallel with
presentation of a staging hypothesis for further research re- advances in neurochemistry, histology, electron microscopy,
lated to the use of biomarkers to identify people with changes neuroanatomy, molecular biology, genetics, and imaging.
in the brain consistent with those seen later in MCI and AD The critical event that set the stage for this approach was
dementia. An important point for all three stages is that the the 1977 seminal workshop (published in 1978) organized
workgroups have created a framework for research on the re- by the NINCDS, NIA, and National Institute of Mental
lationship of the underlying pathophysiology to the emergence Health, chaired by Robert Katzman, Robert Terry, and
of clinical symptoms. In addition, for MCI and AD dementia, Katherine Bick [3].
basic diagnostic criteria for use in current clinical practice are Subsequently, in 1978, the NIA began to build its extramu-
presented. ral program on AD by focusing on developing the infrastruc-
The purpose of this editorial is to provide a brief historic ture and tools for such clinical-pathological studies. The
context to the significance of the proposed revisions to the institute placed high priority on developing, standardizing,

1552-5260/$ - see front matter 2011 The Alzheimers Association. All rights reserved.
doi:10.1016/j.jalz.2011.04.003
254 Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256

and validating various assessment instruments, diagnostic pathological relationships was the need for infrastructure
procedures, as well as fostering the formulation of distinct di- to promote/facilitate multisite collaborative studies on:
agnostic criteria for clinical workup and neuropathological
 Validation the diagnostic criteria with neuropathologi-
evaluation [46]. These early efforts by NIA led to the
cal evaluation/other biomarkers.
creation of an array of quantitative measures of cognition.
 Standardization (including measures ofreliability,
Other program initiatives, which promoted the validation of
sensitivity, specificity) various clinical assessment in-
instruments for objective evaluation of symptoms, were
struments.
critical preliminary steps in developing the capabilities of
 Construction of new measurements for tracking
the field for systematic characterization of the AD
changes in behaviors and symptoms of various do-
syndrome. These early efforts to encourage the
mains of cognition.
development and validation of the necessary tools and
infrastructure for assessment of the disease took time, but Several of the programs and initiatives launched by NIA
also became the foundation for much of the current routine during the period of 1978 to 2011 (e.g., Centers Program,
clinical-workup, and set the standard for clinical staging Consortium to Establish a Registry for Alzheimers Disease
methods as an essential element of clinical criteria. [CERAD], Alzheimers Disease Clinical Studies [ADCS],
One of the other critical barriers for systematic clinico- Alzheimers Disease Neuroimaging Initiative [ADNI])
pathological studies was the lack of widely agreed upon cri- were designed, in part, to enable the development and valida-
teria for the neuropathological evaluation of putative cases of tion of quantitative objective assessment technologies and al-
people with AD syndrome, as compared with healthy aging gorithms for earlier and earlier detection of the AD syndrome.
brains. This problem was addressed by a Research Planning For example, the Alzheimers Disease Patient Registry Pro-
Workshop on Diagnosis of Alzheimers Disease, organized gram was launched in 1986 to address the goal of developing
by NIA in 1983 (published in 1985 [4]).The recommenda- standardized diagnostic assessments. This program included
tions of this workshop led to several program initiatives the CERAD led by Al Heyman and Gerda Fillenbarum, the
that prepared the ground for the next 27 years of research Mayo Clinic Registry led by Len Kurland and Ron Peterson,
on clinico-pathological correlations, as well as some of the the Seattle site led by Eric Larson, the Mon valley project with
issues covered by the current NIA-Alzheimers Association Lewis Kuller and Mary Ganguli, and Denis Evanss group in
Dx criteria presented in this issue. For example, the Neuropa- East Boston. The CERAD project was successful in establish-
thology Panel of NIAs 1983 workshop on AD-Dx took the ing uniform methods for the diagnosis and assessment of AD
first step toward defining the minimum microscopic criteria because of the dedicated and effective leadership provided by
necessary for histological diagnosis of AD. The Neurology Al Heyman and the cooperation of clinicians and investiga-
Panel suggested that the term Alzheimer Disease be tors nationwide and worldwide. Overall, the Alzheimers
reserved for patients who show a compatible clinical course Disease Patient Registry program was instrumental not
along with the histopathological and neurochemical changes only in the development of assessment instruments/proce-
associated with the disease. The panel also considered the dures for standardization but also in helping to refine the con-
problem of distinguishing AD from benign senescent forget- cept mild cognitive impairment.
fulness (mild cognitive impairment) and non-AD-type During the last 27 years, the improvements in the accuracy
dementia. Other topics and recommendations of this work- of the clinical diagnosis have been remarkable. The proce-
shop included neuroimaging, biomarkers, molecular genet- dures for clinical assessment and differential Dx-AD steadily
ics, longitudinal studies, brain banks, establishment of advanced toward well-validated algorithms for identification
family registries and pedigree studies, animal models, and of positive clinical phenotypes of the diseases. Early diagno-
the need for research on normal brain aging. sis has become one of the most important clinical accom-
Before 1984, in the absence of specific diagnostic criteria plishments with profound implications for: (1) research, (2)
for AD, the Diagnostic and Statistical Manual of Mental Dis- establishing the prevalence of AD, (3) initiating treatment
orders (DSM-III/IV) criteria [7] for diagnosis of dementia when it may have optimal benefit, and (4) understanding
had fulfilled the requirements of clinical research. Finally, the pathobiology of the disease. There is a general consensus
this need was addressed with the dual publications of: (a) that many of the advances in diagnosis, treatment(s), care,
NINCDS-ADRDA Diagnostic Criteria [1] and (b) NIAs and understanding the cause(s) would not have been possible
Diagnosis of Alzheimers Disease [4]; these two corollary without the creation of instruments, criteria, infrastructure,
criteria specified not only inclusion/exclusion factors with and programs that support interdisciplinary research. Some
three levels of confidence (McKhann criteria [1]) but of the spectacular clinical and research strides are attribut-
also an objective quantitative measure for histopathological able in large measure to the NIA initiatives since 1978.
confirmations (Khachaturian criteria [4]with its subse- Thus, the publication of these newly revised criteria by the
quent revisions [8,9]). NIAAlzheimers Association workgroups on diagnostic
After the challenges of developing criteria and objective guidelines for Alzheimers disease has not only written the
assessment instruments were overcome, the next major im- coda for a prolonged history of scientific efforts to character-
pediment for advancing knowledge on the clinical- ize the clinical features of dementia but it has also brought the
Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256 255

field to the threshold of a new frontierthe struggle toward The field is ready now to consider different conceptual
primary prevention [10]. The new challenges for the field models for neurodegenerative diseases (e.g., System Fail-
are no less ambitious or difficult to overcome as compared ure Model for Complex Disease of the Brain). The core
with those that were confronted three decades ago when de- premise for such a shift in thinking is based on the proposition
mentia was an obscure neurological condition confused with that the expression of key clinical features in neurodegener-
senility. However, the field cannot wait for another three de- ative diseases (e.g., impairments in memory, movement or
cades for a re-evaluation of the protocols for characterizing mood) are a reflection of a systems failure, of a complex neu-
the AD syndrome in its various stages of progression. ral network, rather than due to a single etiologic factor. This
The following are some suggestions for consideration by type of a model for the pathogenesis of the disease requires
the NIAAlzheimers Association workgroups on diagnostic a drastic shift in research and development priorities beyond
guidelines for Alzheimers disease: the problems of protein cleavage and aggregation.
Thus, the validation of such conceptual model, of a com-
 The workgroups should be chartered by NIA and Alz-
plex disease/syndrome such as AD, will rely on developing
heimers Association to remain active for an indefinite
multiple strategies aimed at preserving/maintaining the func-
period and commissioned to publish revisions at regular
tionality of the system. In the case of AD the system
intervals (34 years) and/or when substantial numbers
could be defined by the synaptic functionality or viability
of subjects (e.g., 5000) have been evaluated with the
of a neuronal network or global malfunction of well-defined
new criteria. Thus, the current amendments to the crite-
anatomical structure. The operational framework for such
ria should be considered as work-in-progress; repre-
a model does not rely on a single etiologic factor. Rather,
senting only the beginning of a new process for regular
this embedded-set model approach requires understanding
re-evaluation/ revisions rather than an end in itself.
the functional relationships among key components of a sys-
 The workgroups should adopt a formal nomenclature
tem and identifying approaches to optimize the functioning
for these criteria and its revisions (e.g., similar to
of the overall system by examining the character of its consti-
DSM).
tutive components. Present notions about the neurobiology of
 The membership of the workgroups should be ex-
dementia, which have enjoyed nearly universal acceptance
panded to reflect international perspective and related
during the last three decades, have proven to be inadequate
ancillary disciplines.
in providing effective targets for treating complex disease.
 The NIA-Alzheimers Association should develop
One explanation for the lackluster performance of current
a multisite collaborative program or initiative for
drug development paradigms might be the failure of the pre-
formal evaluation/validation of the new criteria in
vailing ideas about the pathogenesis of the disease to provide
a proactive manner either through existing programs
a complete account of relationship between the clinical
(e.g., ADC, ADCS, ADNI) or the launch of a new pro-
and biological phenotypes of the disease. The current revi-
gram.
sion of the criteria was largely based on the prevailing con-
 As a prelude to the next reiteration to the criteria, the
ceptual model of dementia/AD, which is increasingly being
field needs to re-evaluate the current conceptual model
questioned and found to be inadequate.
of the disease/syndrome and consider alternative
Future revisions of the criteria, especially when intended
models. The most compelling reason for a new model
to promote trials for prevention, will require the adoption of
of pathogenesis is the need to address the issue of
new thinking (or models) about the full spectrum of patho-
mixed pathologies, which increasingly appear to be
genesis. The new models need to: 1) fully incorporate the
the norm in the general population. The next model
temporal lag between the initiating pathological event and
of pathogenesis (and Dx-AD criteria) needs to take
the first appearance of symptoms; 2) provide complete [or
this into account such questions as: 1) how do several
better] explanations for the biological underpinnings of the
pathologies interact with each other in pre and clinical
key clinical features of the disease (e.g., loss of memory
phases; and 2) how do they all contribute to symptom
and overall deterioration of cognitive functions); and 3)
development?
identify new or different therapeutic target.
Currently, there is growing recognition that the neurobio-
logical processes associated with AD syndrome start many Zaven S. Khachaturian
years before the appearance of any measurable clinical signs Editor-in-Chief*
or impairments of function. Thus, the new challenge for for- Alzheimers & Dementia: The Journal of the
mulating future revisions to the Dx-AD criteria is to move Alzheimers Association
the bar for discriminating the affected from unaffected President, Campaign to Prevent Alzheimers Disease
on into the unknown territory of identifying asymptomatic by 2020 [PAD2020]
people at elevated risk for the disease in the preclinical Rockville, MD, USA
stages. The primary Achilles heel for the future revision *Corresponding author: Tel.: 301-309-6730
of the criteria will be the accuracy or utility of current model Fax: 301-309-6724
of pathogenesis and conceptual model of the syndrome. E-mail address: adj@kra.net
256 Z.S. Khachaturian / Alzheimers & Dementia 7 (2011) 253256

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