"Should Mild Cognitive Impairment Be Regarded as a Normal Part of Aging or as a Clinical Entity Worthy of Treatment?: Presented at AAT"
By Chris Berrie
GENEVA, SWITZERLAND -- April 21, 2006 -- Whether mild cognitive impairment (MCI) should be considered a normal part of aging or a clinical entity that is worthy of treatment depends on the criteria for the definition of the term and implementation of these criteria, according to a presentation during a round-table meeting that took place here April 20[th at the 9th International Geneva/ Springfield Symposium on Advances in Alzheimer Therapy (AAT).
This meeting, titled "Controversies in cholinergic therapy for mild cognitive impairment and Alzheimer's disease," was designed to review some of the current controversies surrounding the use of cholinesterase inhibitor therapy in patients with Alzheimer's disease (AD).
Jeffrey Cummings, MD, professor of neurology and director, Alzheimer's Disease Research Centre, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, United States, who chaired the meeting, stressed that, "What we have chosen are controversial subjects, and these are not areas where there are necessarily going to be answers that we will all agree with, as they are dynamic areas that are evolving in the area of Alzheimer's disease research."
Jodey Corey-Bloom, MD, PhD, professor of neurosciences and staff physician, Alzheimer's Disease Research Centre, University of California, San Diego, California, United States, started her presentation by saying that whether MCI is considered a normal part of aging or a clinical entity that is worthy of treatment would depend on how MCI is defined -- as amnestic MCI (aMCI) or as a wider concept -- and on the intent behind the definition.
The definition of MCI depends on the criteria for MCI and the implementation of these criteria, she said, and stressed the importance of the source of subjects -- whether they come from specialised clinics or the general population -- and the reference standards for normal performance.
This also parallels the intent behind the definition of MCI. As Dr. Corey-Bloom indicated, if this is to include an examination of the prevalence of cognitive impairment and progression in community populations, MCI might be thought of as a normal part of aging. Conversely, MCI might be considered a clinical entity if it is to be used to identify subjects with a high risk of progression to dementia, in terms of defining incipient AD, such as for use in treatment trials.
"The concept of MCI at its core is really cognitive impairment without dementia", she said, but she noted that this comes from a standard of 'normalcy', of the normal aging process, while in the specialised memory clinic, this is actually centred around the pathology of the condition, of the dementia known as AD. "Thus, MCI in the dementia clinic or in the homogeneous setting of the memory clinic is really a 'push-back' from Alzheimer's disease," to aid in earlier, prepathology diagnosis, she said.
To support this, she focussed on the Personne Agées QUID (PAQUID) population-based study (Larrieu et al. 2002) that started from a baseline of 84% normal, 4% aMCI, and 13% other types of nonclinical dementia (OCIND) among the 1654-subject cohort. In the 2-year follow-up period, although some 30% to 40% within each of the aMCI and OCIND populations had reverted to a normal rating, 19% and 16%, respectively had also progressed to dementia, demonstrating the need for MCI-based clinical trials, Dr. Corey-Bloom said.
On the other hand, there has been a lot of progress recently in identifying individuals who can be classified as aMCI, with the clinical phenotype of very mild AD that has an over-representation of the APOE e4 allele, in the setting of the memory clinic and according to strict criteria, such as the Petersen criteria. This has been seen in a number of studies that defined a series of biological markers which show that these subjects are distinctly different from those with AD. These markers are intermediate but significantly elevated levels of CSF tau (Marayama et al. 2001), hypometabolism on cerebral [18F] fluorodeoxyglucose positron emission tomography (PET) imaging (Drzezga et al. Neurology. 2005:64;102-7), and presence of hippocampal atrophy determined by premorbid magnetic resonance-based volume measurements (Jack et al. 1999).
"I think probably the most compelling evidence, though, is the neuropathological evidence," she said, and pointed to the recent demonstration that the neuropathology of aMCI does indeed parallel very early AD (Markesbury et al. 2006), as seen following the quantification of nerve fibrillary tangles and neuritic plaques in specific brain regions of MCI and early AD patients. She also emphasised that these levels are significantly different in MCI patients compared with normal controls.
Dr. Corey-Bloom indicated that there are further challenges that need to be met in future clinical MCI trials. These include not only to obtain better information on the natural course of MCI, but also to design clinical trials that will provide for more homogeneous samples, genetic markers, central spinal fluid markers and neuroimaging, optimal treatment duration, and multidimensional and reliable outcome measures that go beyond the AD Assessment Scale cognitive subscale (ADAS-cog), to give better characterisation of global function, better assessment of high-order instrumental activities of daily living, and to provide further biological markers.
Eisai Europe Ltd. and Pfizer Inc. sponsored this meeting. Dr. Corey-Bloom also acknowledges the receipt of grants/research support from Elan, Wyeth, Ono, and Amarin Pharmaceuticals.
[Presentation title: Should Mild Cognitive Impairment Be Regarded as a Normal Part of Aging or as a Clinical Entity Worthy of Treatment? Combined Abstract 19]
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