Deterioro cognitivo leve. Criterios diagnósticos.

Deterioro cognitivo leve. Criterios diagnósticos.

(Mild cognitive impairment: Diagnosis criteria. )

Ricardo F. Allegri.

Servicio de neuropsicología (SIREN), y Unidad de Investigación “Rene Barón” del Instituto Universitario CEMIC, Buenos Aires, Argentina

En el presente trabajo se exponen los criterios diagnósticos del deterioro cognitivo leve, su evolución en el tiempo y su estado actual.

There is a clinical cognitive continuum from normal aging through to AD. Cognitive decline without dementia has been commonly considered to be a normal consequence of brain aging, but it can also indicate the onset of dementia. The boundary between normal aging and very early AD is becoming a central focus of research. The pre-dementia diagnosis is intimately connected with the development of therapies to prevent AD.
Many attempts have been made to define the cognitive decline associated with ageing. The idea of ageing-effects versus disease is not new; in 1962, Kral et al. described the “benign senescent forgetfulness” (BSF) in which fairly unimportant details of an experience (e. g. a name, a place or a date) are not recalled but do not interfere with activities of daily life and does not progress to dementia. Kral (1978) also recognized that “differentiation of the benign and malignant types of senescent forgetfulness does not necessarily mean that there are two neuro-pathological processes”. These diagnostic criteria were not precise, and were not validated in controlled longitudinal studies.  
These cognitive changes in aging have been assigned various terms, such as age associated memory impairment (Crook et al. 1986), late-life forgetfulness (Blackford & La Rue 1989) and aging-associated cognitive decline (Levy, 1994). These terms have been used largely to explain the extremes of normal aging, to characterize individuals who are not normal but not demented. Such terms were criticized for their imprecision.
Mild cognitive impairment was initially described in the late 1990s by Flicker and colleagues (Flicker et al. , 1991, 1993) and was related to persons who qualified for stage 3 on the Global Deterioration Scale (GDS; Reisberg et al. 1982) or 0. 5 on the Clinical Dementia Rating (CDR; Hughes, 1982). Reisberg et al. , 2008 identifies mild cognitive impairment as a clinical stage on the GDS. Petersen says it is important to note that GDS and CDR are severity rating scales and not diagnostic instruments. Both stages may correspond to MCI or may describe individuals with very mild dementia (Petersen, 2000). He proposed a clinical continuum from normal aging through mild cognitive impairment to Alzheimer´s disease. MCI wasn´t normal aging: this construct was supposed to be a clinical description of persons who were destined to develop AD (Petersen et al. , 1999).
The identification of persons at risk of developing dementia, and Alzheimer´s disease in particular, is of major economic importance, particularly if preventive strategies or therapeutic action are to be developed. This challenge explains the popularity of the concept of MCI and its wide application in the epidemiological, clinical, paraclinical and therapeutic domains (Portet et al. , 2006).  
Mild cognitive impairment was original defined as the transitional state that can precede dementia but the condition and the rates of conversion remain controversial.  
The objective of our review will be to consider the question of whether MCI is a well enough established syndrome to be a diagnosis in medical practice and a valid target of therapy.
Mild cognitive impairment applies to individuals who have some cognitive impairment but are not sufficiently debilitated as to warrant the diagnosis of dementia or AD. An individual with MCI typically develops memory deficit and soon exhibits other cognitive abnormalities without functional impairment. Petersen et al. , 1999 provided a landmark in the “rediscovery” of the entity, as well as the popularization of the terminology.  
The original diagnostic criteria for Mild Cognitive Impairment (Petersen, et al. , 1999) were:
1. Memory complaint, preferably corroborated by an informant
2. Memory impairment relative to age-matched and education-matched healthy people
3. Preserved general cognitive function
4. Intact activities of daily living
5. Not clinically demented

The tests to detect memory impairment were not specified but memory impairment was defined as performance more than 1. 5 standard deviations (SD) below normative values.  
Petersen et al. , 1999 used the term MCI to define individuals with symptomatic and progressive memory impairment that share many features with early AD (Morris, 2001).
More recently, MCI measures have been expanded since clinicians observed non-memory related symptoms in some persons. The Canadian Study of Health and Aging (a longitudinal, population-based study of aging) defined “cognitive impairment not demented (CIND)” to characterize individuals who are cognitively abnormal but not demented (Graham et al. , 1997). In many aspects CIND resembles MCI, but the CIND label includes a broader subset of population with cognitive impairment.
De Kosky and Chertkow (2001) proposed 3 subtypes of MCI: amnestic MCI (which is said to progress preferentially to Alzheimer´s disease), multiple domain MCI (which may represent normal aging or may progress to vascular cognitive impairment or neurodegenerative disorder), and single domain non-amnestic MCI (which may progress to fronto-temporal dementia, Lewy Bodies Dementia or Alzheimer Disease).  
It is clear that the chosen definition of cognitive impairment will have a major effect on estimates of prevalence. This impact could also extend to prognosis although these definitions describe syndromes and make no claim to cause (DeCarli, 2003).
Petersen (2004) described original criteria for MCI that were specific to isolated deficits in memory; clinical and research developments have extended these criteria to include a broad range of cognitive deficits and clinical subtypes with many potential causes. This concept has been challenged both by those whose studies suggest that MCI is, in fact, early or incipient AD (Morris, 2006) and by those who find that MCI is an unstable condition with poor predictive validity for AD (Ritchie et al. , 2001; Whitehouse 2007).  
Supporting studies are underway to determine whether amnestic and non-amnestic subtypes of MCI have different prognoses for progression to dementia and which type of dementia they predict (Petersen, 2005).
The following symptomatic criteria were formulated and put forth by the international working group on MCI (Winblad et al. , 2004): “1. The individual is neither normal nor demented; 2. There is evidence of cognitive deterioration, shown by either objectively measured decline over time or subjective report of decline by self or informant in conjunction with objective cognitive deficits; 3. Activities of daily life are preserved and complex instrumental functions are either intact or minimally impaired. These criteria expand the construct of MCI to cognitive domains outside of memory and present MCI as a prodrome to multiple types of dementia (Gauthier et al. , 2006).  
Artero et al. , 2006 validated the newly revised criteria for Mild Cognitive Impairment, but incorporate the possibility of change in activity level and alteration of non-amnesic cognitive functions. A significantly more reliable detection of transition to dementia was obtained with MCI-R than with previous MCI criteria.  
Based on the memory profile (information has been registered but cannot be retrieved, even with the use of facilitation techniques (cueing)), Dubois and Albert (2004), defined one subtype of MCI which leads to AD before the occurrence of the fully developed clinical dementia syndrome.  
The presence of AD in its earliest, pre-dementia stages may be detectable by use of specific memory tests like the Free and Cued Selective Recall Reminding Test (Buschke, 1984), which distinguishes the different mechanisms of registration, storage, and retrieval of information. When impaired free recall is associated with even a small amount of cueing on recall, many intrusions and false positives on recognition tasks are highly suggestive of AD – this condition is commonly referred to as “amnestic syndrome of hippocampal type” (Dubois and Albert, 2004; Allegri et al. , 2005; Harris et al. , 2001; Sarazin et al. , 2007).  
Based on neuropsychological profiling Dubois and Albert (2004) proposed the following new diagnostic criteria for MCI of Alzheimer-type or prodromal AD: memory complaints by the patients or by the family; progressive onset; normal or mildly impaired complex activities of daily living; amnesic syndrome of the “hippocampal type” defined by very poor free recall despite adequate (and controlled) encoding, decreased total recall because of insufficient effect of cueing or impaired recognition, numerous intrusion; persistence of memory changes at a subsequent assessment; absence of the fully developed syndrome of dementia; and lastly, exclusion of other disorders that may cause MCI .  
Impaired memory tests are defined by scores 1. 5 standard deviation (SD) below normative values. It is important to emphasize that the 1. 5 SD limits of MCI means that impairment can only be detected when recall is very low, and impairment is late and severe. Therefore, memory impairment defined by low recall according to recall norms cannot detect pre-symptomatic early cognitive (memory) impairment, when declining performance is still in the normal range, and, by definition, MCI cannot detect early impairment, but can only detect severe late impairment.

Sarazin et al (2007) found that the Free and Cued Selective Recall Reminding Test for verbal episodic memory (Buschke, 1984, Grober and Buschke, 1987; Grober, et al. , 1988; Buschke et al. , 1997) appears to be the best neuropsychological test for detecting AD at its prodromal stage.
The construct of MCI has been challenged both by those whose studies suggest that MCI is, in fact, early or incipient AD (Morris et al. 2001; Petersen et al 1999) and by those who find that MCI is an unstable condition with poor predictive validity for AD (Ritchie et al. , 2001; Whitehouse 2007). Some forms of MCI, like the amnestic type, are more likely to progress to AD, whereas other MCI subtypes progress to other type of non-Alzheimer dementia. Whitehouse (2007) argues that this alleged empirical and conceptual progress was simply an acknowledgment of the logical necessity that every progressive dementia must have an early phase that is characterized by milder symptoms than those that would impair activities of daily living. MCI was originally described as pre-AD syndrome (Petersen et al. , 1999) but recently has been used to refer to a pre-dementia (e. g. AD, vascular dementia, fronto-temporal dementia) stage or to normal aging (Petersen, 2004, 2007). Despite many consensus conferences, experts cannot agree on critical aspects of the label MCI, particularly on its clinical utility (Whitehouse, 2007). After a major attempt at consensus published in Lancet (Gauthier et al. , 2006), an email survey revealed that only 57% of the workshop participants believed that the term MCI should be used clinically (Whitehouse and Brodaty 2006). There is a fragility of the broad MCI concept when one attempts to operationalize it strictly in test performance.  
One of the proposed advantages of MCI has been its potential usefulness for clinical trials directed at delaying the time to onset AD, but with only small variations in the inclusion criteria for MCI, four trials (MIS, InDDEx, Gal-Int 11 and Rofecoxib) have had very wide-ranging annual rates of progression to AD dementia (Dubois et al, 2007).  
In this light, MCI cannot be seen as pre-Alzheimer construct; rather, it is cognitive impairment with preserved activities in daily living. We need better identification of prodromal AD. Current definitions of MCI are quite diverse. They put forth a variety of prognoses and pathologies, which leads to some confusion in the literature (DeCarli, 2003).

References

• Allegri, R. F. , Butman, J. , Arizaga, R. L. , Machnicki, G. , Serrano, C. , Taragano, F. E. , Sarasola, D. , Lon, L. (2007). Economic impact of dementia in developing countries: an evaluation of costs of Alzheimer-type dementia in Argentina. International Psychogeriatrics, 19 (4), 705-718.
• Allegri, R. F. , Drake, M. , Harris, P. , Serrano, C. M. , Taragano, F. E. (2005). Intrusions in Verbal Learning in Mild Cognitive Impairment: Prodromal Alzheimer´s Disease?. Neurology, 65 (Suppl 1), A165.
• Allegri, R. F. , Sarasola, D. , Serrano, C. M. , Taragano, F. E. , Arizaga, R. L. , Butman, J. L. , Loñ, L. (2006). Neuropsychiatric Symptoms as a Predictor of Caregiver Burden in Alzheimer’s disease. Neuropsychiatric Disease and Treatment, 2 (1), 105-110.
• APA (American Psychiatric Association) (1994). Diagnostic and Statistical Manual of Mental Disorders, DSM-IV, Washington, DC.
• Artero, S. , Petersen, R. , Touchon, J. and Ritchie, K. (2006). Revised Criteria for Mild Cognitive Impairment: Validation within a Longitudinal Population Study. Dementia and Geriatric Cognitive Disorders, 22, 465-470.  
• Belleville, S. (2008). Cognitive training for persons with mild cognitive impairment. International Psychogeriatrics, 20, 57-66.
• Blackford, R. C. , La Rue, A. (1989). Criteria for diagnosis AAMI: proposed improvement from the field. Developmental Neuropsychology, 5, 295-306.
• Brookmeyer, R. , Gray, S. , Kawas, C. (1998). Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health, 88 (9), 1337-1342.
• Buschke, H. (1984). Cued recall in amnesia. Journal of Clinical Neuropsychology, 6, 433-440.
• Buschke, H. , Sliwiski, M. J. , Kuslansky, G. , Lipton, R. B. (1997). Diagnosis of early dementia by the Double Memory Test: encoding specificity improves diagnostic sensitivity and specificity. Neurology, 48, 989-992.
• Crook, T. , Bartus, R. T. , Ferris, S. H. , Whitehouse, P. , Cohen, G. D. , Gershon, S. (1986). Age associated memory impairment: proposed diagnostic criteria and measures of clinical change. Report of a National Institute of Mental Health work group. Developmental Neuropsychology, 2, 261-276.
• De Carli, Ch. (2003). Mild cognitive impairment: prevalence, prognosis, aetiology and treatment. Lancet Neurology, 2, 15-21.
• De Kosky, S. T. , Chertkow, H. M. (2001). Just forgetfulness or onset of Alzheimer’s disease. Plenary session of AAN may 2001.  
• Dubois, B. (2000). Prodromal Alzheimer´s disease: a more useful concept than mild cognitive impairment?. Current Opinion in Neurology, 18, 367-369.
• Dubois, B. , Feldman, H. , Jacova, C. , DeKosky, S. , Barberger-Gateau, P. , Cummings, J. L. , Delacourte, A. , Galasko, D. , Gauthier, S. , Jicha, G. , Meguro, K. , O'brien, J. , Pasquier, F. , Robert, P. , Rossor, M. , Salloway, S. , Stern, Y. , Visser, P. J. , Scheltens, P. (2007). Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurology, 6(8), 734-46.
• Dubois, B. and Albert, M. L. (2004). Amnestic MCI or prodromal Alzheimer’s disease? Lancet Neurology, 3, 246-248.
• Dubois, B. (2000). “Prodromal Alzheimer’s disease”: a more useful concept than mild cognitive impairment?. Current Opinion in Neurology, 18, 367-369.  
• Feldman, H. H. , Ferris, S. , Winblad, B. , Sfikas, N. , Mancione, L. , He, Y. (2007). Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurology, 6, 501-512.
• Flicker, C. , Ferris, S. H. , Reisberg, B. (1993). A two year longitudinal study of cognitive function in normal aging and Alzheimer´s disease. Journal of Geriatric Psychiatry and Neurology, 6, 84-96.
• Flicker, C. , Ferris, S. H. , Reisberg, B. (1991). Mild cognitive impairment in the elderly: predictors of dementia. Neurology, 41, 1006–1009.
• Ganguli, M. , Dodge, H. H. , Shen, C. , DeKosky, S. T. (2004). Mild cognitive impairment, amnestic type: an epidemiological study. Neurology, 63, 115-121.
• Ganguli, M. (2006). Mild Cognitive Impairment and the 7 Uses of Epidemiology. Alzheimer Disease and Associate Disorders, 20(3 Suppl 2), S52-7.
• Gauthier, S. , Reisberg, B. , Zaudig, M. , Peretsen, R. , Ritchie, K. , Broich, K. , Belleville, S. , Brodaty, H. , Bennett, D. , Chertkow, H. , Cummings, J. L. , de Leon, M. , Feldman, H. , Ganguli, M. , Hampel, H. , Scheltens, P. , Tierney, M. C. , Whitehouse, P. , Winblad, B. International Psychogeriatric Association Expert Conference on mild cognitive impairment. (2006). Mild Cognitive Impairment. Lancet, 367, 1262-1270.  
• Gold, M. , Wang, D. , Truyen, L. (2003). Galantamine for the treatment of mild cognitive impairment: 2 double blind, placebo-controlled studies. International Psychogeriatrics, 15(suppl. 2), 259.
• Graham, J. E. , Rockwood, K. , Beattie, B. L. , Eastwood, R. , Gauthier, S. , Tuokko, H. , McDowell, I. (1997) Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet, 349, 1793-1796.
• Grober, E. , Buschke, H. (1987). Genuine memory deficits in dementia. Developmental Neuropsychology, 3, 13-36.
• Grober, E. , Buschke, H. , Crystal, H. , Bang, S. & Dresner, R. (1988). Screening for dementia by memory testing. Neurology, 38, 900-903.  
• Hansson, O. , Zetterberg, H. , Buchhave, P. , Minthon, L. , Warkentin, S. (2006). Association between CSF biomarkers and incipient Alzheimer’s disease in patients with MCI: a follow-up study. Lancet Neurology, 5, 228-234.
• Harris, P. , Drake, M. , Allegri, R. F. (2001). deterioro Cognitivo leve: en búsqueda de la pre-demencia. Acta Psiquiátrica y Psicológica de América Latina, 47 (1), 11-20.
• Helmer, C. , Pasquier, F. , Dartigues, J. F. (2006). Epidemiology of Alzheimer disease and related disorders. Medecine Sciences (Paris), 22(3), 288-96.  
• Hughes, C. P. , Berg, L. , Danziger, W. L. , Coben, L. A. and Martin, R. L. (1982). A new clinical scale for staging of dementia. British Journal of Psychiatry, 140, 566-572.
• Jack, C. R. Jr. , Petersen, R. C. , Xu, Y. C. , O'Brien, P. C. , Smith, G. E. , Ivnik, R. J. , Boeve, B. F. , Waring, S. C. , Tangalos, E. G. , Kokmen, E. (1999). Prediction of AD with MRI based hippocampal volume in mild cognitive impairment. Neurology, 52, 1397-1403.
• Jelic, V. , Kipivelto, M. , Winblad, B. (2006). Clinical trials in mild cognitive impairment: lessons for the future. Journal of Neurology Neurosurgery and Psychiatry, 77, 429-438.
• Klunk, W. E. , Engler, H. , Nordberg, A. , Bacskai, B. J. , Wang, Y. , Price, J. C. , Bergström, M. , Hyman, B. T. , Långström, B. , Mathis, C. A. (2004). Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Annals of Neurology, 55, 306-319.
• Kral, A. V. (1962). Senescent forgetfulness: Benign and Malignant. Canadian Medical Association Journal, 86, 257-260.  
• Kral, A. V. (1978). Benign senescent forgetfulness. In R. Katzman, R. D. Terry, and K. L. Bick (eds), Alzheimer’s Disease: Senile Dementia and Related Disorders (aging, Vol 7), Raven Press, New York , pp 47-*51.
• Larrieu, S. , Letenneur, L. , Orgogozo, J. , Fabrigoule, C. , Amieva, H. , Le Carret, N. , Barberger-Gateau, P. , Dartigues, J. F. (2002). Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology, 2002, 59, 1594–99.
• Laurent, B. , Anterion, C. , Allegri, R. F. (1998). Memorie et demence. Revue Neurologique (Paris), 154 (Suppl 2), S33-49.  
• Laurent, B. , Thomas Anterion, C. (2002). Incertitudes et limites du MCI: apport de la neuropsychologie. Revue Neurologique (Paris); 158: 10, 5S11-5S20.
• Levy, R. (1994). Ageing-associated decline. Psychogeriatrics, 6, 63-68.
• Mc Khann, G. , Drachman, D. , Folstein, M. , Katzman, R. , Price, D. and Stadlan, E. M. (1984). 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, 34(7), 939-944.  
• Morris, J. C. , Storandt, M. , Miller, J. P. , McKeel, D. W. , Price, J. L. , Rubin, E. H. , Berg, L. (2001). Mild cognitive impairment represents early stage Alzheimer’s disease. Archives of Neurology, 58, 397-405.  
• Morris, J. C. (2006). Mild cognitive impairment is early stage Alzheimer disease – Time to revise diagnostic criteria. Archives of Neurology, 63, 15-16.  
• Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183-194.  

• Petersen, R. C. , Morris, J. C. (2005). Mild Cognitive Impairment as a clinical entity and treatment target. Archives of Neurology, 62, 1160-1163.  
• Petersen, R. C. , Parisi, J. E. , Dickson, D. W. , Johnson, K. A. , Knopman, D. S. , Boeve, B. F. , Jicha, G. A. , Ivnik, R. J. , Smith, G. E. , Tangalos, E. G. , Braak, H. , Kokmen, E. (2006). Neuropathology of amnesic mild cognitive impairment. Archives of Neurology, 63, 665-672.  
• Petersen, R. C. , Smith, G. E. , Ivnik, R. J. , Tangalos, E. G. , Schaid, D. J. , Thibodeau, S. N. , Kokmen, E. , Waring, S. C. , Kurland, L. T. (1995). Apolipoprotein E status as a predictor of development of Alzheimer’s disease in memory impaired individuals. JAMA, 273, 1274–1278.
• Petersen, R. C. , Smith, G. E. , Waring, S. C. , Ivnik, R. J. , Tangalos, E. G. , Kolmen, E. (1999). Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology, 56, 303–308.
• Petersen, R. C. , Thomas, R. G. , Grundman, M. , Bennett, D. , Doody, R. , Ferris, S. , and Alzheimer's Disease Cooperative Study Group. (2005). Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment. New England Journal of Medicine, 2005; 352: 2378-88.  
• Petersen, R. C. (2007). Mild Cognitive Impairment: Current Research and Clinical Implications. Seminars in Neurology, 27, 22-31.  
• Petersen, R. C. (2000). Mild cognitive impairment or Questionable Dementia. Archives of Neurology, 57, 643–644.
• Portet, F. , Ousset, P. J. , Visser, P. J. , Frisoni, G. B. , Nobili, F. , Scheltens, Ph. (2006). Mild cognitive impairment in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer’s disease. Journal of Neurology Neurosurgery and Psychiatry, 77, 714-718.
• Rabins, P. V. , Lyketsos, C. G. , Steele, C. (1999). Practical Dementia Care. New York, NY: Oxford University Press; 1999.
• Reisberg, B. , Ferris, S. H. , de Leon, M. J. , Crook, T. (1982). The Global Deterioration Scale for assessment of primary degenerative dementia. American Journal of Psychiatry, 139, 1136-1139.
• Reisberg, B. , and Gauthier, S. (2008). Current evidence for subjective cognitive impairment (SCI) as the pr-mild cognitive impairment (MCI) stage of subsequently manifest Alzheimer’s disease. International Psychogeriatrics, 20, 1-16.
• Reisberg, B. , Ferris S. H. , Kluger, A. , Franssen, E. , Wegiel, J. , and de Leon, M. J. (2008). Mild cognitive impairment (MCI): a historical perspective. International Psychogeriatrics, 20, 18-31.
• Ritchie, K. , Artero, S. and Touchon, J. (2001). Classification criteria for mild cognitive impairment A population-based validation study. Neurology, 56, 37–42
• Rockwood, K. , Chertkow, H. , Feldman, H. H. (2007). Is Mild Cognitive Impairment a Valid Target of Therapy?. Canadian Journal of Neurological Sciences, 34 (suppl. 1), S90-96.  
• Sarazin, M. , Berr, C. , De Rotrou, J. , Fabrigoule, C. , Pasquier, F. , Legrain, S. , Michel, B. , Puel, M. , Volteau, M. , Touchon, J. , Verny, M. , Dubois, B. (2007). Amnestic syndrome of the medial temporal type identifies prodromal AD: A longitudinal study. Neurology, 69, 1859-1867.  
• Serrano Medicina Serrano CM, Allegri RF, Caramelli P, Taragano F, Camera L. deterioro Cognitivo Leve. Encuesta sobre Actitudes de Médicos Especialistas y Generalistas. Medicina (BsAs) 2007; 67 (1): 19-25.  
• Whitehouse, P. J. and Brodaty, H. (2006). Mild cognitive impairment. Lancet , 367, 1979.
• Whitehouse, P. J. (2007). Mild cognitive impairment- a confused concept?. Nature, 3(2), 62-63.
• Winblad, B. , Palmer, K. , Kipivelto, M. , Jelic, V. , Fratiglioni, L. , Wahlund, L. O. , Nordberg, A. , Bäckman, L. , Albert, M. , Almkvist, O. , Arai, H. , Basun, H. , Blennow, K. , de Leon, M. , DeCarli, C. , Erkinjuntti, T. , Giacobini, E. , Graff, C. , Hardy, J. , Jack, C. , Jorm, A. , Ritchie, K. , van Duijn, C. , Visser, P. , Petersen, R. C. (2004). Mild Cognitive Impairment: beyonds controversies, towards a consensus-report of the international Working Group on Mild Cognitive Impairment. Journal of Internal Medicine, 256, 240-246.