John Morris has re-evaluated the functional ratings of patients entered into the National Alzheimer’s Coordinating Centre in accordance with the New Criteria recently proposed by Albert et al. (1): More than 90 percent of the patients currently diagnosed with mild or very mild Alzheimer’s disease (AD) should be reclassified as having MCI! With this result, John Morris underlines the diagnostic overlap between MCI and early AD, indicating that any distinction between these entities is arbitrary.

MCI is an artificial construct resulting from the implicit rules of the NINCDS-ADRDA criteria for AD (2). The first rule was to define AD as a clinical-pathological entity that can be only ascertained by the evidence of a specific pathology with brain biopsy or postmortem examination. The second rule was the consequence of the previous one: The clinical diagnosis can only be considered as "probable" and can only be made when the disease is advanced and reaches the threshold of dementia. This definition left room for the MCI construct (3). In this context, MCI had the advantage...  Read more

John Morris has re-evaluated the functional ratings of patients entered into the National Alzheimer’s Coordinating Centre in accordance with the New Criteria recently proposed by Albert et al. (1): More than 90 percent of the patients currently diagnosed with mild or very mild Alzheimer’s disease (AD) should be reclassified as having MCI! With this result, John Morris underlines the diagnostic overlap between MCI and early AD, indicating that any distinction between these entities is arbitrary.

MCI is an artificial construct resulting from the implicit rules of the NINCDS-ADRDA criteria for AD (2). The first rule was to define AD as a clinical-pathological entity that can be only ascertained by the evidence of a specific pathology with brain biopsy or postmortem examination. The second rule was the consequence of the previous one: The clinical diagnosis can only be considered as "probable" and can only be made when the disease is advanced and reaches the threshold of dementia. This definition left room for the MCI construct (3). In this context, MCI had the advantage to draw attention to the preclinical stage of demented conditions, but with one major inconvenience: the heterogeneity of the underlying etiologies (4).

During the last two decades, the discovery of biological/neuroimaging biomarkers has radically changed the diagnostic framework of AD. As these biomarkers are considered as surrogate of the histopathological changes of the disease, the clinical diagnosis can now be established in vivo even at a prodromal/pre-dementia stage of the disease. No more reference to dementia is needed, and the diagnosis can be made at a prodromal stage. The classical clinical-pathological entity is now replaced by a clinical-biological entity. This important conceptual shift also includes the early stage of the disease because these biomarkers characterize the disease at any stage. Therefore, AD can now be considered as a clinical and symptomatic entity that encompasses both pre-dementia/prodromal and dementia phases (5). In the case of prodromal AD, the recommended diagnostic procedure was refined in 2010 (5), and it is based on the two following criteria:

1. An early significant episodic memory impairment with the objective evidence of an “amnestic syndrome of the hippocampal type.” This episodic memory impairment can be isolated or associated with other cognitive/behavioral changes as AD advances.

2. The presence of pathophysiological markers either in the CSF (low Aβ and high tau/phospho-tau: both are needed because the absence of one of these no more certifies the diagnosis) or in the brain (with significant retention on PET amyloid radioligand).

In this new conceptual framework, MCI is a diagnostic label that should be now restricted and applied only when patients do not fulfill the criteria for the clinicobiological phenotype of prodromal AD, i.e., when

• the clinical phenotype is not characteristic of AD (amnestic syndrome of the hippocampal type in the case of typical AD; or a specific presentation of atypical cases);
• the biomarkers are not positive or not performed.

This is timely to consider AD as a continuum, starting with the first specific symptoms of the disease. There is no more reason to wait until patients are demented to diagnose AD. Moreover, as underlined by John Morris, the limit between the two stages is arbitrary. Therefore, MCI should remain a waiting stage for mild cognitive disorders from uncertain etiologies, including patients that do not fulfill criteria for prodromal AD.

References:
1. Albert MS, DeKosky ST, Dickson D 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(3):270-279. Abstract

2. McKhann G, Drachman DA, Folstein M et al. Clinical diagnosis of Alzheimer's disease—Report of the the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984;34:939-44. Abstract

3. Petersen RC, Smith GE, Waring SC et al. Mild cognitive impairment: Clinical characterization and outcome. Arch Neurol 1999 March;56:303-8. Abstract

4. Dubois B, Albert ML. Amnestic MCI or prodromal Alzheimer's disease? Lancet Neurol 2004 April;3(4):246-8. Abstract

5. Dubois B, Feldman HH, Jacova C et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. Abstract

View all comments by Bruno Dubois

In this paper, John Morris re-evaluated the functional ratings of patients entered into the National Alzheimer’s Coordinating Center and reclassified them in accordance with the definition of “functional independence” allowed by the revised mild cognitive impairment (MCI) criteria (1). Almost all (99.8 percent) of the patients currently diagnosed with very mild Alzheimer’s disease (AD) could be reclassified as having MCI. Morris concludes that the categorical distinction between both entities has been compromised by the revised criteria.

Although the MCI concept has been of great usefulness, contributing from a clinical, neuroimaging, and pathological point of view to the understanding of the symptomatology that may eventually lead to dementia (2), it is probably now the time to move on into a nosological conceptualization of AD early stages. MCI defines a syndrome, and therefore it may be the consequence of different diseases with distinct etiologies. It is obvious that the revised MCI criteria aim to approximate the syndrome-based concept, MCI, to an etiological one, AD;...  Read more

In this paper, John Morris re-evaluated the functional ratings of patients entered into the National Alzheimer’s Coordinating Center and reclassified them in accordance with the definition of “functional independence” allowed by the revised mild cognitive impairment (MCI) criteria (1). Almost all (99.8 percent) of the patients currently diagnosed with very mild Alzheimer’s disease (AD) could be reclassified as having MCI. Morris concludes that the categorical distinction between both entities has been compromised by the revised criteria.

Although the MCI concept has been of great usefulness, contributing from a clinical, neuroimaging, and pathological point of view to the understanding of the symptomatology that may eventually lead to dementia (2), it is probably now the time to move on into a nosological conceptualization of AD early stages. MCI defines a syndrome, and therefore it may be the consequence of different diseases with distinct etiologies. It is obvious that the revised MCI criteria aim to approximate the syndrome-based concept, MCI, to an etiological one, AD; however, stigma apart, it seems more accurate to diagnose a disease and then stage it. AD has been traditionally conceptualized as a clinicopathological entity, requiring for its definite diagnosis the presence of a characteristic pathology together with a clinical picture of dementia (3). Several biomarkers, for example, cerebrospinal fluid (CSF) Aβ1-42, and tau protein levels, have shown to constitute a specific signature of the underlying AD-pathology in AD patients (4). Therefore, the classical clinical-pathological entity is now replaced by a clinical-biological entity, which means that the ability to diagnose AD in its early stages with the certainty that the underlying biological process is related to AD pathology is becoming a reality (5,6). To some extent, it seems an anachronism to negate this reality and to try to stick to different labels in order to avoid facing an early etiological diagnosis. Furthermore, as John argues, it becomes to some extent arbitrary and “clinician dependent” to make the diagnosis of AD or that of MCI (due to AD with different levels of likelihood). In other medical specialties that will never happen, since they diagnose the disease, for example, cancer, and then stage it.

It is clear that the AD field is moving forward and that the concept of a clinical-biological entity within a continuum that goes from normal cognition to dementia captures this new paradigm (5). There is also increasing evidence that the preclinical stage of the disease is clinically silent but active from a biological and functional perspective (7), and that the diagnosis may only be performed when there are clear and specific symptoms (5). However, this symptomatology may be as mild as an isolated episodic memory dysfunction if properly tested. We should keep in mind that in order to avoid false positive diagnoses, the specificity of the clinical diagnosis is as important as that of the biological one. However, I do not find any reasons, if the patient wants to receive the diagnosis, and while fulfilling the ethical principle of autonomy/respect for patients’ rights, to delay it (8).

The advantages of AD early diagnosis may be numerous from a medical, psychological, research, and social point of view (9). Early diagnosis of AD enables patients who want to know to make decisions about the disease before dementia onset and helps them to prepare psychologically and socially for its onslaught. Additional benefits for patients also include reducing uncertainty about what is happening to them and enabling them to develop better coping abilities in order to avoid crises. The benefits for the caregivers may be related to an increased awareness of the disease and greater time to organize a support plan for the future. From a research point of view, it may become a need, since the development of new disease-modifying drugs depends on performing clinical trials in a very early stage in the absence of dementia.

It is time to move towards a nosological and etiological diagnosis of the early stages of AD. Early diagnosis in the pre-dementia or prodromal stage of the disease may result in considerable benefits for patients who are willing to receive it.

References:
1. Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. 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 May;7(3):270-9. Abstract

2. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303-8. Abstract

3. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. Abstract

Dubois B, Albert ML. Amnestic MCI or prodromal Alzheimer's disease? Lancet Neurol. 2004 Apr;3(4):246-8. Abstract

4. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ, Alzheimer's Disease Neuroimaging Initiative. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol. 2009 Apr;65(4):403-13. Abstract

5. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. Abstract

6. Rami L, Solé-Padullés C, Fortea J, Bosch B, Lladó A, Antonell A, Olives J, Castellví M, Bartres-Faz D, Sánchez-Valle R, Molinuevo JL. Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of prodromal AD. Int J Geriatr Psychiatry. 2012 Feb;27(2):127-34. Abstract

7. Molinuevo JL, Sánchez-Valle R, Lladó A, Fortea J, Bartrés-Faz D, Rami L. Identifying Earlier Alzheimer's Disease: Insights from the Preclinical and Prodromal Phases. Neurodegener Dis. 2011 Dec 7. Abstract

8. Lladó A, Antón-Aguirre S, Villar A, Rami L, Molinuevo JL. [Psychological impact of the diagnosis of Alzheimer's disease]. Neurologia. 2008 Jun;23(5):294-8. Abstract

9. Molinuevo JL, Pintor L, Peri JM, Lleó A, Oliva R, Marcos T, Blesa R. Emotional reactions to predictive testing in Alzheimer's disease and other inherited dementias. Am J Alzheimers Dis Other Demen. 2005 Jul-Aug;20(4):233-8. Abstract

View all comments by José Luis Molinuevo