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Mild cognitive impairment clinical trials

Key Points

  • In recent years, the concept of mild cognitive impairment (MCI) has come to represent a transitional stage between normal ageing and very early Alzheimer's disease (AD).

  • Commonly accepted guidelines for MCI have been established — memory complaint, preferably corroborated by an informant, objective memory impairment for age and education, normal general cognition, preserved activities of daily living, and not demented. The precise definitions need to be explicated, but these will probably simply be a refinement of a concept, rather than a major re-definition.

  • The therapies being explored for MCI essentially mirror the therapeutic strategies being developed for AD: acetylcholinesterase inhibitors, antioxidants, anti-inflammatories, glutamate receptor modulators and nootropics. Immunomodulators and secretase inhibitors could also have potential.

  • Several trials of these therapies in MCI are now in progress, which are discussed here. If any of these trials are positive, in that the agent under study is able to slow the progression to the diagnosis of clinically probable AD or to alter the rate of progression of symptoms, this will have a major impact on treatment of many patients.

  • The challenge will remain to further refine the MCI criteria so that treatments can be targeted toward a specific MCI population and not be expanded to all ageing individuals.

Abstract

Most investigators believe that by the time the clinical diagnosis of Alzheimer's disease has been made, sufficient neuronal damage has taken place in the brain to make reversal of the condition unlikely. Prevention would be a more appealing strategy, but the challenges of conducting true primary prevention trials in asymptomatic persons are formidable. The duration and expense of these types of trial make them unappealing. Large numbers of subjects would need to be followed for many years, and without a promising therapeutic agent, this approach would be risky. Hence, the concept of secondary prevention treatment trials involving minimally symptomatic individuals, such as persons with mild cognitive impairment (MCI) — a transitional stage between normal ageing and very early Alzheimer's disease — has evolved and seems more promising. This concept has led to the emergence of a number of clinical trials for MCI, which are discussed here.

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Figure 1: Theoretical change in cognitive function as a person progresses to Alzheimer's disease.
Figure 2: The overlap among clinical diagnostic criteria for MCI and AD and corresponding ratings on CDR and GDS.
Figure 3: Clinical and aetiological heterogeneity of MCI.
Figure 4

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Acknowledgements

I would like to thank Ms. Donna Asleson for her expert secretarial assistance with the manuscript. This work was supported by grants from the National Institute on Aging (AG 06786, AG 1657, AG 10483).

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Petersen, R. Mild cognitive impairment clinical trials. Nat Rev Drug Discov 2, 646–653 (2003). https://doi.org/10.1038/nrd1155

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