Clinical trials in mild cognitive impairment: lessons for the future

Karolinska Institutet, Neurotec Department, Division of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden.
Journal of Neurology Neurosurgery & Psychiatry (Impact Factor: 5.58). 05/2006; 77(4):429-38. DOI: 10.1136/jnnp.2005.072926
Source: PubMed

ABSTRACT Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.

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Available from: Vesna Jelic, Sep 02, 2014
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    • "Any intervention in AD requires the consideration of adverse events and side effects. While pharmacological treatments have not altered course of disease or improved function [4] [5], they are associated with adverse side effects particularly gastrointestinal issues (i.e., vomiting, nausea, and diarrhea). In contrast , CT has no reported side effects in adults with healthy and impaired cognitive function [16] [19] [32]. "
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    ABSTRACT: There is much interest in early intervention for the prevention or postponement of dementia in Alzheimer's disease (AD). The results of drugs trials in this regard have thus far been disappointing, and non-pharmacological interventions are receiving increased attention. One such intervention is complex cognitive activity. Evidence from epidemiological studies suggests that participation in stimulating mental activities is associated with lowered dementia risk. The introduction of novel and complex cognitive interventions to healthy adults and those with cognitive impairment may represent an efficacious treatment option to improve cognition, lower dementia incidence, and slow rate of decline. This review examines the evidence for restorative cognitive training (CT) and addresses a number of clinically relevant issues regarding cognitive benefit and its transfer and persistence. Although the number of randomized controlled trials is limited, preliminary evidence suggests that CT may provide immediate and longer term cognitive benefits which generalize to non-trained domains and non-cognitive functions, with supervised small group multi-domain training providing greatest benefits. Possible neuroplastic mechanisms are discussed, and recommendations for further research and clinical implementation provided.
    Journal of Alzheimer's disease: JAD 08/2014; 42(Suppl 4):S551-S559. DOI:10.3233/JAD-141302 · 3.61 Impact Factor
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    • "Despite of the new consideration of MCI as an unstable condition, there is still solid evidence supporting the higher risk of conversion to dementia (especially AD) in this group of patients (Bennett et al. 2005; Gauthier et al. 2006; Morris et al. 2001). Therefore, the early detection of MCI is still a critical issue regarding the development of interventions to prevent or delay the process of neurodegeneration (Jelic et al. 2005). In order to attain such goal, it is important to bear in mind that clinical subtypes of MCI are not only associated with different etiologies but also with a more or less rapid conversion to dementia (Brodaty et al. 2012; Tabert et al. 2006). "
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    ABSTRACT: Mild cognitive impairment (MCI) has been described as an intermediate stage between normal aging and dementia. Previous studies characterized the alterations of brain oscillatory activity at this stage, but little is known about the differences between single and multidomain amnestic MCI patients. In order to study the patterns of oscillatory magnetic activity in amnestic MCI subtypes, a total of 105 subjects underwent an eyes-closed resting-state magnetoencephalographic recording: 36 healthy controls, 33 amnestic single domain MCIs (a-sd-MCI), and 36 amnestic multidomain MCIs (a-md-MCI). Relative power values were calculated and compared among groups. Subsequently, relative power values were correlated with neuropsychological tests scores and hippocampal volumes. Both MCI groups showed an increase in relative power in lower frequency bands (delta and theta frequency ranges) and a decrease in power values in higher frequency bands (alpha and beta frequency ranges), as compared with the control group. More importantly, clear differences emerged from the comparison between the two amnestic MCI subtypes. The a-md-MCI group showed a significant power increase within delta and theta ranges and reduced relative power within alpha and beta ranges. Such pattern correlated with the neuropsychological performance, indicating that the a-md-MCI subtype is associated not only with a "slowing" of the spectrum but also with a poorer cognitive status. These results suggest that a-md-MCI patients are characterized by a brain activity profile that is closer to that observed in Alzheimer disease. Therefore, it might be hypothesized that the likelihood of conversion to dementia would be higher within this subtype.
    Age 02/2014; 36(3). DOI:10.1007/s11357-014-9624-5 · 3.45 Impact Factor
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    • "cognitive impairment (MCI) (Petersen et al. 2001). Clinical trials of AChE-Is for the treatment of cognitive deficits of MCI have been uniformly negative (Jelic et al. 2006). It is now recognized that MCI is an etiologically heterogeneous state with only approximately 60 – 70% of patients having underlying AD (Jicha et al. 2006). "
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    ABSTRACT: In this work we consider marketed drugs for Alzheimer disease (AD) including acetylcholinesterase inhibitors (AChE-Is) and antiglutamatergic treatment involving the N-methyl-d-aspartate (NMDA) receptor. We discuss medications and substances available for use as cognitive enhancers that are not approved for AD or cognitive impairment, and other neurotransmitter-related therapies in development or currently being researched. We also review putative therapies that aim to slow disease progression by mechanisms not directly related to amyloid or tau.
    Cold Spring Harbor Perspectives in Medicine 03/2012; 2(3):a006395. DOI:10.1101/cshperspect.a006395 · 7.56 Impact Factor
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