Clinical and Health Affairs
New Clinical Criteria for the Alzheimer’s Disease Spectrum
By Ronald C. Petersen, Ph.D., M.D.
■ New criteria for diagnosing Alzheimer’s disease (AD) were recently published. These criteria cover the entire spectrum of AD including dementia due to AD, mild cognitive impairment due to AD, and preclinical AD. A major feature of the new criteria is that they distinguish between the clinical characteristics of the disorder and the pathological features. Earlier criteria were based on clinical features alone. The new criteria include the use of imaging and other biomarkers to aid in diagnosis. The criteria regarding clinical features are currently being used in practice; the criteria regarding biomarkers still need to be validated.
In 1984, a landmark paper was published by McKhann and colleagues outlining criteria for diagnosing Alzheimer’s disease (AD).1 About the same time, the National Institute on Aging established its AD program, and research centers around the country began embracing the diagnostic criteria. The criteria were readily adopted in clinical practice as well and have been used to diagnose Alzheimer’s disease for the past 25 years.
The original criteria focused on the patient’s history and the results of cognitive testing. Imaging was used primarily to rule out other disorders such as tumors, cerebral infarcts, and normal pressure hydrocephalus. Although seemingly simplistic at this point in time, these criteria have served the research and clinical communities very well. In fact, there has been a strong correlation between diagnoses made using these criteria and neuropathological evidence at autopsy in patients who have been followed longitudinally.2 The criteria (or variations of them) have been used in many clinical trials for AD and have contributed to the approval of five drugs for the disorder by the Food and Drug Administration.3 They also have influenced thinking about dementia and AD. For example, the characterization of dementia in the last several iterations of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, DSM-III-R, DSM-IV, and DSM-IV-TR) has been strongly influenced by the McKhann criteria. In fact, some have suggested the construct of dementia has been “Alzheimer-ized” over the years.4 Nevertheless, the McKhann criteria for AD have dominated our approach to research involving large cohorts of subjects.5
During the last three decades, we have learned a great deal about the pathophysiology of AD.6 Research, including studies involving Mayo Clinic investigators, has yielded information that led some to call for a revision of the criteria. In 2009, the National Institute on Aging and the Alzheimer’s Association formed international work groups to revise the diagnostic criteria for AD, and in 2011, new criteria and guidelines that update, refine, and broaden the ones published in 1984 were issued. This article presents the rationale for issuing the new guidelines and discusses some of the key differences between the new and old approaches to diagnosing this disease.
The Old Versus the New Criteria
The most notable features of the new diagnostic criteria and guidelines are that they add criteria from existing guidelines for diagnosing mild cognitive impairment (MCI) and expand the conceptual framework for thinking about Alzheimer’s disease to include a “preclinical” stage characterized by biological changes (biomarkers) that occur years before any disruptions in memory, thinking, or behavior can be detected. The new guidelines do not yet specify which biomarkers should be considered signatures of preclinical Alzheimer’s disease. Instead, they propose a research agenda and a framework for eventually adding biomarker benchmarks to the diagnosis of Alzheimer’s disease in all of its stages.
Using the old criteria and guidelines, a person had to have clinical symptoms such as progressive memory impairment and other cognitive difficulties that are severe enough to affect daily functioning and harbor pathological features commensurate with AD before they could be diagnosed with the disease. This is similar to requiring a cardiac patient to have a symptom such as angina before a diagnosis of coronary artery disease can be made. As researchers began to learn more about what was occurring in the brains of people with AD, they discovered that the clinical symptoms of AD emerged after a preclinical period, during which a specific disease process was taking place. Consequently, the revised criteria refer to a clinical spectrum (Alzheimer’s disease-clinical or AD-C) and a pathological spectrum (AD-pathophysiology or AD-P).
The new criteria and guidelines also allow for a more definitive diagnosis. In 1984, diagnosing AD was largely a matter of exclusion. That is, if the person had progressive cognitive impairment, an evaluation was undertaken to be certain that the cause was not related to factors such as vascular disease, normal-pressure hydrocephalus, tumors, or other medical comorbidities. Only if no other cause was found was a diagnosis of AD made. Now, making a diagnosis is an exercise of inclusion, in which the clinician looks for a clinical course fulfilling positive criteria for the diagnosis.7 Eventually, clinicians will also look for specific biomarkers of the pathological process.8
The new criteria and guidelines also better reflect distinctions between AD and other forms of dementia. In addition to the knowledge about the underlying pathophysiology of AD that has amassed in recent years, there is a great deal of new information regarding other types of dementia as well. For example, we now know more about vascular cognitive impairment, and several attempts have been made to refine the criteria for this diagnosis.9 We also have a better understanding of dementia with Lewy bodies, and sophisticated criteria have been published and revised allowing for the rather precise characterization of this disorder.10 In addition, the overlap of dementia with Lewy bodies with Parkinson’s disease-dementia and the more recently described Parkinson’s disease-mild cognitive impairment (MCI) with coexisting AD pathophysiology have been studied.11 And, recently, frontotemporal lobar degeneration has been characterized and subtyped.12 Although the diagnostic criteria for these conditions are still evolving, the behavioral and language variants have been carefully characterized. The distinguishing clinical features and biomarkers of these entities are being investigated to allow further differentiation of these disorders from AD.
The New Model
We now understand that a sequence of events occurs prior to clinical manifestations of AD, which include cognitive and functional impairment. A major advance has been the development of a hypothetical model of those events.13
The model presumes that the deposition of amyloid in the brain initiates development of the disease. Numerous theories explain how amyloid gets deposited, but most consider fibrillization an early event. The deposition of amyloid can be detected in the cerebrospinal fluid (CSF) as low Aβ42 or with positron emission tomography (PET) imaging using a radiolabeled ligand for amyloid.14 After the amyloid is deposited extracellularly, neuronal injury results. The first manifestation of this can be detected as an increase in CSF tau. Tau is an intracellular protein that becomes hyperphosphorylated in AD; its release during neurodegeneration can be detected in the CSF. Later, metabolic abnormalities occur that can be detected by fluorodeoxyglucose positron emission tomography; subsequent structural volumetric changes, which can be measured on MRI, then take place. It is only after these events have occurred that clinical symptoms begin to manifest first in cognition and, later, in daily functioning.
It should be emphasized that, although it is based on an increasing number of studies of the biomarkers of AD, this is still a theoretical model. Yet it serves as the foundation for the new criteria and guidelines, which propose that clinical criteria be augmented with testing for biomarkers.15
The new criteria and guidelines divide the AD spectrum into three phases. The phase of greatest clinical impairment is “dementia due to AD.” The intermediate stage is “mild cognitive impairment due to AD.” And the stage designated “preclinical AD” refers to the point at which the patient is clinically asymptomatic but harbors biomarkers suggestive of a developing AD-P.16
■ Dementia Due to AD
This is the phase that most closely resembles AD as it was diagnosed using the 1984 criteria.7 It should be noted, however, that memory impairment is no longer an absolute requirement for a diagnosis of probable AD and, thus, there are subtle differences between the old and new criteria regarding the clinical presentations. Although having memory impairment represents the most common presentation of clinical dementia, there can be atypical presentations such as a prominent visuospatial deficit seen in posterior cortical atrophy or the logopenic form of aphasia.17 These uncommon, but well-recognized, clinical phenotypes often have AD-P as the underlying cause, and the new criteria accommodate them.
The core criteria for a dementia diagnosis include a cognitive impairment in two or more domains including memory, language, executive function, or visuospatial skills accompanied by a disruption of daily function. If these criteria are met and insidious onset and gradual progression of the symptoms are corroborated by someone who knows the person well, a diagnosis of probable AD dementia is made. The amnestic presentation often prevails; but nonamnestic presentations can occur.
The novel features of the new criteria are outlined in Table 1. Initially, a clinical diagnosis of probable AD is made if the criteria for dementia are met and information from imaging or fluid biomarkers is unavailable or uninformative. The next level of certainty for a probable AD diagnosis is evidence of either amyloid deposition (detected on PET or in CSF) or neuronal injury (CSF tau levels, FDG PET, or MRI atrophy patterns). This evidence increases the likelihood that the clinical syndrome of dementia is the result of underlying AD-P. The highest level of certainty is achieved when there is evidence for both amyloid deposition and neuronal injury in the presence of clinical evidence. There is also the category “possible AD,” which is an appropriate diagnosis if the patient presents with an atypical clinical course but has both types of biomarkers—amyloid deposition and neuronal injury. Finally, with the wealth of available information on non-AD dementias, there is the category “unlikely due to AD,” which is appropriate if the person has a clinical syndrome accompanied by negative biomarkers for amyloid deposition and neuronal injury.
It should be noted that at this point, only the diagnosis of probable AD dementia should be used in practice. All of the other criteria listed in Table 1 need to be corroborated with physiologic evidence before they can be used.
■ Mild Cognitive Impairment
Due to AD
The criteria for diagnosing MCI caused by AD follow a similar hierarchy.15 Initially, a patient must meet the following criteria: 1) concern raised by the patient, someone who knows the patient well, or by an examining clinician about cognitive function; 2) evidence of cognitive decline and impairment in at least one domain such as memory, language, executive function, or visuospatial skills; 3) preservation of functional independence, meaning the person does not need help with activities of daily living; and 4) not meeting the criteria for dementia.
As shown in Table 2, the first level of diagnostic certainty for MCI involves having the clinical evidence alone. The next level of certainty requires positive evidence of either amyloid deposition or neuronal injury. The highest level of confidence that MCI is caused by AD is derived when the clinical syndrome is accompanied by positive evidence for both amyloid deposition and neuronal injury. As with dementia, the likelihood of a clinical syndrome not being caused by AD-P is low if the biomarkers are negative. At this point, only the diagnosis of MCI should be used in practice.
■ Preclinical AD
What may be the most exciting but least supported aspect of the new criteria pertains to a condition called “preclinical AD.”16 None of the diagnostic recommendations are ready for use in clinical practice; but these criteria outline a rich research agenda. Stage 1 refers to the presence of amyloid deposition without evidence of neuronal injury or subtle cognitive change (Table 3). Stage 2 refers to the presence of amyloid deposition and neuronal injury but without cognitive changes. Stage 3 uses the same biomarker criteria as Stage 2 but also includes subtle cognitive signals representing a change. A recent Mayo Clinic study applying the preclinical criteria to a population-based sample of subjects 70 to 89 years of age in Olmsted County, Minnesota, found that approximately 30% fulfilled the criteria for Stages 1-3.18 Another 43% had no evidence of amyloid deposition, neuronal injury, or subtle cognitive changes; these individuals are considered to be aging normally. Interestingly, many individuals showed evidence of either neuronal injury and/or cognitive changes but were negative with regard to amyloid deposition. These participants were designated as having a suspected nonamyloid pathway or SNAP.
Conclusion
The new criteria issued in 2011 for diagnosing the AD spectrum were designed to advance the field from both a research and clinical perspective. The recommendations incorporate the dominant theoretical model of AD-C and AD-P and delineate criteria to reflect this. These new criteria are designed to help clinicians characterize individuals as early as possible in the course of their disease to allow for early intervention and prevention of subsequent neuronal damage. The criteria are also necessary for designing clinical trials for new therapies to prevent neuronal destruction. A great deal of research will be needed to validate these criteria, and numerous studies are currently underway throughout the world. MM
Ronald Petersen is director of the Mayo Alzheimer’s Disease Research Center.
The author would like to thank David Cahill for his assistance in preparing this manuscript. This work has been supported by the National Institute on Aging: P50 AG016754, U01 AG006768 and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Clinic.
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