Alzheimer’s & Dementia 7 (2011) 328–329
Commentary on “Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” New criteria for a new era Constantine G. Lyketsos* Johns Hopkins University, Baltimore, MD, USA
The publication in Alzheimer’s & Dementia of new criteria for preclinical Alzheimer’s disease (AD) , mild cognitive impairment (MCI)  due to AD, and dementia due to AD  represents the dawning of a new era in our field. Coupled with the groundbreaking recommendation of an advisory panel to the Food and Drug Administration regarding marketing approval for florbetapir in the diagnosis of AD , we move into a period during which attention is shifted from the diagnosis of a single syndrome to the staging of a complex disease and its clinical manifestations. These exciting developments are tempered by the public health emergency related to the anticipated emergence of 115 million new cases of dementia worldwide in the next 40 years , whereas the most recent drug development efforts have been disappointing and are seriously challenging the amyloid hypothesis. The new criteria represent a major advance because they establish certain principles. The first principle established is the distinction of clinical syndromes due to brain disease from their causes in the brain—in the past, the term dementia was often used to refer to a syndrome and a brain disease at the same time. Consistent with evidence produced since the last AD criteria, MCI and dementia are unequivocally defined as syndromes existing entirely in the clinical realm, diagnosable purely on clinical grounds. They are recognized as heterogeneous entities, MCI more heterogeneous than dementia, typically caused by underlying brain disease, with what we call AD being a principal cause. At the same time, an initial attempt is made to define when AD pathology assessed in vivo should be considered as the prime or, at least, major contributing cause to the occurrence of MCI or dementia. It is in the latter that the criteria fall short by not adequately spelling out causal rules for the attribution of cognitive syndromes to the presence of the underlying pathology. This challenge arises since much, if not most, of the *Corresponding author:Tel.: 410-550-0062; Fax: 410-550-1407. E-mail address: [email protected]
time several underlying pathologies are present in dementia, each contributing partly to the occurrence of the clinical picture . Such are the limits of our knowledge and of our ability to quantify causal relationships between brain pathology and clinical conditions in living people. The second principle is established by setting a much broader boundary for these cognitive syndromes. This is an implicit recognition that specific clinical manifestations of brain disease represent damage to specific brain circuits affected rather than the processes damaging or leading to malfunction of these areas . In complex heterogeneous conditions such as AD, in which several brain areas are affected, clinical manifestations are broad and typically include symptoms in the behavioral realm (depression, psychosis, apathy, agitation), which are nearly unive-rsal in people with dementia and extremely common in all types of MCI . Further, by moving away from a purely “memory centric” view of cognitive syndromes, the new criteria stre-ngthen the ability of clinicians and researchers to investigate and treat the non-AD dementias. The third principle established relates to how these criteria stage the AD brain disease and its delayed but parallel clinical manifestations . Operating under the strong, but yet unproven, amyloid hypothesis, biomarkers of amyloid and neuronal degeneration are used in tandem with type and severity of clinical manifestations to define five stages of AD brain disease: abnormal amyloid plaque deposition in the brain without neurodegeneration or clinical manifestations (stage I); amyloid deposition with neurodegeneration but no clinical manifestations (stage II); amyloid deposition, neurodegeneration, and subtle nonfunctional clinical manifestations detectable only through very sensitive assessments (stage III); amyloid deposition, neurodegeneration with mild clinical manifestations in cognition or behavior but where functioning is largely preserved (stage IV-“MCI due to AD”); and finally, amyloid deposition, neurodegeneration, with functionally effective clinical manifestations in cognition and behavior (stage V-“dementia due to AD”).
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C.G. Lyketsos / Alzheimer’s & Dementia 7 (2011) 328–329
These five stages of AD will from now on be, at least until disproven by data, the bread-and-butter language we use in patient care and research. What are the next steps? Important work remains in translating these new criteria into definitive therapeutic advances. Getting there will require at minimum three key activities. The first critical step is harmonization with other criteria. Although these are being published in 2011, the American Psychiatric Association is working on a 2013 revision of its Diagnostic and Statistical Manual, in which a different language is being used to classify essentially the same syndromes . It is important that harmonization be pursued between these criteria to prevent confusion and so that collaboration between the fields working in this area is further advanced. Similar harmonization is necessary between these criteria and those produced by specialty societies for other conditions that lead to cognitive disorders, and with the International Classification of Diseases. The second critical step is the standardization of biomarker measures. This is absolutely necessary for the clinical and research application of the new criteria: it is an urgent priority. It seems that the Food and Drug Administration advisory panel has recommended that the developer of florbetapir define clear cutoffs, using objective standards that establish abnormal amounts and distributions of the tracer in the brain. At the very least, this allows for use of the same standards in different centers. Such standardization must be accomplished for other brain imaging (e.g., hippocampal atrophy) and cerebrospinal fluid biomarkers. The third critical step is for the field to move beyond amyloid, especially because it seems that some forms of amyloid will soon be quantifiable routinely in living patients. The new staging approach articulates the position, really still a very good hypothesis, that processes downstream to amyloid are critical to the emergence of symptoms and disability. Amyloid is not sufficient in many people as a cause of clinical disease and its removal may carry risks that are hard to overcome. Consequently, we must grow our understanding of downstream processes such as inflammation, oxidative injury, lipid misprocessing , and insulin resistance to mention a few. Of course these may turn out to be upstream from amyloid, or in a self-reinforcing cycle with amyloid misprocessing. It is through understanding variability in the processes of clearing amyloid and how amyloid mis-processing or deposition leads to neuronal injury, and then symptoms, that we will ultimately achieve the success we are seeking: subtyping the heterogeneous diseases we call AD in such a way that is ultimately therapeutically relevant.
One way to stay focused on these aforementioned steps is for the National Institute of Aging working with the Alzheimer’s Association to define a process for regular updates of these criteria. This update might occur, for example, every 5 years for the purposes of harmonization and incorporation of new evidence derived from biomarker standardization and other advances. This process should also spell out how these criteria will be updated, and what sorts of additional evidence are needed so that the criteria become increasingly more evidence-based. Such a systematic, transparent, inclusive effort is the field’s best bet for advances in nosology, which will eventually lead to definitive therapeutic successes.
References  Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:280–92.  Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging– Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:270–9.  McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging– Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263–9.  Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). J Nucl Med 2010;51:913–20.  Alzheimer’s Disease International. World Alzheimer’s Report, 21, 2009. Available at: http://www.alz.co.uk/research/files/ WorldAlzheimerReport-ExecutiveSummary.pdf. Accessed March 26, 2011.  White L, Small BJ, Petrovitch H, Ross GW, Masaki K, Abbott RD, et al. Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia aging study. J Geriatr Psychiatry Neurol 2005;18:224–7.  Lyketsos CG. Lessons from Neuropsychiatry. J Neuropsychiatry Clin Neurosci 2006;18:445–9.  Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment. JAMA 2002;288:1475–83.  Rabins PV, Lyketsos CG. A commentary on the proposed dsm revision regarding the classification of cognitive disorders. Am J Geriatr Psychiatry 2011;19:201–4.  Mielke MM, Lyketsos CG. Alterations of the Sphingolipid Pathway in Alzheimer’s Disease: New Biomarkers and Treatment Targets? Neuromolecular Med 2010;12:331–40.