734 http://neurology.thelancet.com Vol 6 August 2007 Position Paper Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria Bruno Dubois*, Howard H Feldman*, Claudia Jacova, Steven T DeKosky, Pascale Barberger-Gateau, Jeffrey Cummings, André Delacourte, Douglas Galasko, Serge Gauthier, Gregory Jicha, Kenichi Meguro, John O’Brien, Florence Pasquier, Philippe Robert, Martin Rossor, Steven Salloway, Yaakov Stern, Pieter J Visser, Philip Scheltens The NINCDS–ADRDA and the DSM-IV-TR criteria for Alzheimer’s disease (AD) are the prevailing diagnostic standards in research; however, they have now fallen behind the unprecedented growth of scientific knowledge. Distinctive and reliable biomarkers of AD are now available through structural MRI, molecular neuroimaging with PET, and cerebrospinal fluid analyses. This progress provides the impetus for our proposal of revised diagnostic criteria for AD. Our framework was developed to capture both the earliest stages, before full-blown dementia, as well as the full spectrum of the illness. These new criteria are centred on a clinical core of early and significant episodic memory impairment. They stipulate that there must also be at least one or more abnormal biomarkers among structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of amyloid β or tau proteins. The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of amyloid β as well as at the hyperphosphorylation state of tau. Validation studies in existing and prospective cohorts are needed to advance these criteria and optimise their sensitivity, specificity, and accuracy. Background For research purposes, the diagnosis of Alzheimer’s disease (AD) is based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV-TR) 1 and the National Institute of Neurological Disorders and Stroke–Alzheimer Disease and Related Disorders (NINCDS–ADRDA) working group. 2 These accepted criteria are fulfilled in a two- step diagnostic process where there is initial identification of a dementia syndrome and then the application of criteria based on the clinical features of the AD phenotype. The DSM-IV-TR criteria require the presence of both a memory disorder and impairment in at least one additional cognitive domain, both of which interfere with social function or activities of daily living (ADL). 1 ADL impairment has come to define the threshold for the diagnosis of dementia beyond the identification of a cognitive abnormality. The NINCDS–ADRDA clinical criteria of probable AD do not require evidence of interference with social or occupational functioning but they include the specification that the onset of AD is insidious and that there is a lack of other systemic or brain diseases that may account for the progressive memory and other cognitive deficits. The currently accepted criteria support a probabilistic diagnosis of AD within a clinical context where there is no definitive diagnostic biomarker. A definite diagnosis of AD is only made according to the NINCDS–ADRDA criteria when there is histopathological confirmation of the clinical diagnosis. 2 Since the publication of the NINCDS–ADRDA criteria in 1984, the elucidation of the biological basis of AD has advanced greatly, allowing an unprecedented under- standing of the disease process. The clinical phenotype of AD is no longer described in exclusionary terms, but can be characterised more definitively on a phenotypic basis. Distinctive markers of the disease are now recognised including structural brain changes visible on MRI with early and extensive involvement of the medial temporal lobe (MTL), molecular neuroimaging changes seen with PET with hypometabolism or hypoperfusion in temporoparietal areas, and changes in cerebrospinal fluid biomarkers. A driving force behind this emerging identity of AD has been the intense research interest in characterising the earliest stages of AD that predate the crossing of the dementia threshold, defined by functional disability. Prodromal AD (see glossary, panel 1) must be distinguished within the broad and heterogeneous state of cognitive functioning that falls outside normal ageing. 3 This state has been described by a wide range of nosological terms including age-associated memory impairment, age-related cognitive decline, age-associated cognitive decline, mild cognitive disorder, mild neurocognitive disorder, cognitively impaired not demented, and mild cognitive impairment. 4–9 Mild cognitive impairment (panel 1) is the most widely used diagnostic term for the disorder in individuals who have subjective memory or cognitive symptoms, objective memory or cognitive impairment, and whose activities of daily living are generally normal. Progression to clinically diagnosable dementia occurs at a higher rate from mild cognitive impairment than from an unimpaired state, but is clearly not the invariable clinical outcome at follow-up. 10 A more refined definition of AD is still needed to reliably identify the disease at its earliest stages. The case for revising the research criteria for AD diagnosis There are several factors that highlight the need to update the current research criteria for AD. Lancet Neurol 2007; 6: 734–46 Published Online July 9, 2007 DOI:10.1016/S1474- 4422(07)70178-3 See Reflection and Reaction page 667 INSERM U610, Hpital de la Salpêtrière , Paris, France, and Université Pierre et Marie Curie–Paris6, Paris, France (B Dubois MD); Division of Neurology, University of British Columbia and Vancouver Coastal Health, Vancouver BC, Canada (H H Feldman MD, C Jacova PhD); Department of Neurology, University of Pittsburgh, Pittsburgh, USA (S T Dekosky MD); INSERM U593, Université Victor Segalen Bordeaux 2, France (P Barberger-Gateau MD); University of California at Los Angeles Alzheimer’s Disease Center, USA (J Cummings MD); CHU de Lille, Centre INSERM JPA, Bâtiment Gérard Biserte, Lille, France (A Delacourte PhD); Department of Neurosciences, University of California, San Diego, California, USA (D Galasko MD); McGill Center for Studies in Aging, Douglas Hospital, Montreal, Quebec, Canada (S Gauthier MD); Department of Neurology; University of Kentucky Medical Center; Sanders-Brown Center on Aging; Lexington, USA (G Jicha MD); Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan (K Meguro MD); Wolfson Research Centre, Institute for Ageing and Health, Newcastle General Hospital, Newcastle upon Tyne, UK (J T O’Brien MD); Neurology Department, Memory Clinic, Lille University Hospital, France (F Pasquier MD); Centre Mémoire de Ressources et de Recherche, Pavillon M, Hôpital Pasteur, Nice, France (P Robert MD); Dementia Research Group, Department of