. Operationalization of mild cognitive impairment: a graphical approach. PLoS Med. 2007 Oct;4(10):1615-9. PubMed.


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  1. The report by Matthews and colleagues from the Medical Research Council Cognitive Function and Ageing Study raises important issues regarding mild cognitive impairment (MCI): 1) it has been an important concept for the field; 2) it has been difficult to operationalize; and 3) there is substantial non-uniformity and inconsistency in diagnostic criteria for MCI, with resultant heterogeneity in sample characteristics and clinical outcomes. However, the authors mistakenly consider that MCI represents "an intermediate stage of cognitive decline between normal and pathological brain aging." This concept simply is not supported by the pathobiology of Alzheimer disease (AD), which is the underlying disorder for the largest subset of MCI. Neuropathological lesions in AD develop in the absence of symptoms in nondemented elders until some threshold of neuronal deterioration is reached and/or cognitive reserve is overcome to allow the initial symptoms of AD, including those characterized as MCI, to be expressed (Troncoso et al., 1996; Hulette et al., 1998; Price and Morris,1999; Barnes et al., 2006). For the subset of individuals meeting MCI criteria for whom the minimal cognitive deficits represent the earliest symptomatic stages of AD, neuropathological AD already is fully established (Morris et al., 2001; Markesbery et al., 2006; Storandt et al., 2006). The concept expressed by Matthews et al. that MCI occurs in a transition zone between normal and pathological brain aging ignores this literature.

    The elaborate diagnostic scheme as shown in the flow diagram proposed by Matthews and colleagues similarly ignores the underlying pathology of the conditions they attempt to classify. A far more useful contribution would be to exercise clinical judgment for individuals with cognitive complaints and provide an etiologically based diagnosis such that individuals could be classified on the basis of the suspected underlying pathology believed to be responsible for the cognitive condition. In this way, there would be MCI of the Alzheimer type, or of the vascular dementia type, or of the diffuse Lewy body type, etc., or of the non-neurodegenerative type (e.g., cognitive adverse effects of medications). The likeliest cause or causes of the cognitive complaints would be identified. Longitudinal follow-up and clinicopathological studies would inform as to whether the original classifications were accurate or not, thus helping to advance the field by improving the ability to accurately identify dementing disorders in their earliest symptomatic stages. This approach is eminently feasible and surprisingly accurate in identifying the subset of MCI individuals for whom the mild cognitive deficits are the initial clinical manifestation of underlying AD (e.g., Storandt et al., 2006). In fact, for this subset, the MCI designation should be discarded in favor of an etiologically-based diagnosis to reflect what it represents: early-stage AD (Morris, 2006).


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    . Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J Neuropathol Exp Neurol. 1998 Dec;57(12):1168-74. PubMed.

    . Neuropathologic substrate of mild cognitive impairment. Arch Neurol. 2006 Jan;63(1):38-46. PubMed.

    . Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001 Mar;58(3):397-405. PubMed.

    . Mild cognitive impairment is early-stage Alzheimer disease: time to revise diagnostic criteria. Arch Neurol. 2006 Jan;63(1):15-6. PubMed.

    . Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.

    . Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI. Neurology. 2006 Aug 8;67(3):467-73. PubMed.

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