Advertisement

Mild cognitive impairment: An opportunity to identify patients at high risk for progression to Alzheimer's disease

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Background:

      There is increasing evidence that subtle losses in cognitive function may be symptomatic of a transition to early Alzheimer's disease (AD). Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD. Of the MCI subtypes, patients with amnestic MCI (a-MCI) are at greatest risk.

      Objectives:

      The objectives of this article were to review the relationship between MCI, normal aging, and AD, and to summarize recent research on the diagnosis and potential treatment of MCI.

      Methods:

      Relevant articles were identified through searches of MEDLINE and EMBASE using the terms mild cognitive impairment; cognitive impairment, no dementia; and dementia prodrome, with no restrictions as to year. Additional papers of interest were identified from the reference lists of the identified articles. The search was current as of February 2006.

      Results:

      Guidelines and recommendations are being developed to assist physicians in diagnosing MCI, identifying its subtype and etiology, understanding the risks for conversion to AD, and managing disease progression. Given the existence of a subset of individuals with a-MCI, who are at greatest risk for progression to AD but still have high levels of cognition and function, the ability to improve symptoms and delay progression to AD would be particularly beneficial. In a 3-year, randomized, double-blind, placebo-controlled study in 769 patients with a-MCI, treatment with the cholinesterase inhibitor donepezil was associated with a significantly lower rate of progression to AD compared with placebo during the first 12 months of treatment (hazard ratio=0.42; 95% CI, 0.24–0.76; P=0.004) but not at later time points. Of other types of agents that have been investigated (antioxidants, estrogen replacement therapy, cyclooxygenase-2-selective inhibitors), none have shown significant beneficial effects in delaying cognitive decline or progression to AD. New drugs such as secretase inhibitors, small molecules that disrupt amyloid aggregation, and immunotherapies are in preclinical development.

      Conclusions:

      MCI involves more substantial cognitive and memory decline than normal aging and represents a significant risk factor for the development of dementia. Further research is needed into treatments to delay the conversion from MCI to AD.

      Key words

      To read this article in full you will need to make a payment
      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Petersen RC
        Mild cognitive impairment as a diagnostic entity.
        J Intern Med. 2004; 256: 183-194
        • Petersen RC
        • Doody R
        • Kurz A
        • et al.
        Current concepts in mild cognitive impairment.
        Arch Neurol. 2001; 58: 1985-1992
        • Hsiung GY
        • Sadovnick AD
        • Feldman H
        Apolipoprotein E epsilon4 genotype as a risk factor for cognitive decline and dementia: Data from the Canadian Study of Health and Aging.
        CMAJ. 2004; 171: 863-867
        • Petersen RC
        • Stevens JC
        • Ganguli M
        • et al.
        Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology.
        Neurology. 2001; 56: 1133-1142
        • Tabert MH
        • Albert SM
        • Borukhova-Milov L
        • et al.
        Functional deficits in patients with mild cognitive impairment: Prediction of AD.
        Neurology. 2002; 58: 758-764
        • Di Carlo A
        • Baldereschi M
        • Amaducci L
        • et al.
        Cognitive impairment without dementia in older people: Prevalence, vascular risk factors, impact on disability. The Italian Longitudinal Study on Aging.
        J Am Geriatr Soc. 2000; 48: 775-782
        • Ganguli M
        • Dodge HH
        • Shen C
        • DeKosky ST
        Mild cognitive impairment, amnestic type: An epidemiologic study.
        Neurology. 2004; 63: 115-121
        • Graham JE
        • Rockwood K
        • Beattie BL
        • et al.
        Prevalence and severity of cognitive impairment with and without dementia in an elderly population.
        Lancet. 1997; 349: 1793-1796
        • Lopez OL
        • Kuller LH
        • Fitzpatrick A
        • et al.
        Evaluation of dementia in the Cardiovascular Health Cognition Study.
        Neuroepidemiology. 2003; 22: 1-12
        • Ritchie K
        • Artero S
        • Touchon J
        Classification criteria for mild cognitive impairment: A population-based validation study.
        Neurology. 2001; 56: 37-42
        • Devanand DP
        • Folz M
        • Gorlyn M
        • et al.
        Questionable dementia: Clinical course and predictors of outcome.
        J Am Geriatr Soc. 1997; 45: 321-328
        • Flicker C
        • Ferris SH
        • Reisberg B
        Mild cognitive impairment in the elderly: Predictors of dementia.
        Neurology. 1991; 41: 1006-1009
        • Petersen RC
        • Smith GE
        • Waring SC
        • et al.
        Mild cognitive impairment: Clinical characterization and outcome.
        Arch Neurol. 1999; 56 ([published correction appears in Arch Neurol. 1999;56:760]): 303-308
        • Tierney MC
        • Szalai JP
        • Snow WG
        • et al.
        Prediction of probable Alzheimer's disease in memory-impaired patients: A prospective longitudinal study.
        Neurology. 1996; 46: 661-665
        • Petersen RC
        • Thomas RG
        • Grundman M
        • et al.
        • Alzheimer's Disease Cooperative Study Group
        Vitamin E and donepezil for the treatment of mild cognitive impairment.
        N Engl J Med. 2005; 352: 2379-2388
        • Farlow M
        • Anand R
        • Messina Jr, J
        • et al.
        A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease.
        Eur Neurol. 2000; 44: 236-241
        • Raskind MA
        • Peskind ER
        • Wessel T
        • Yuan W
        • Galantamine USA-1 Study Group
        Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension.
        Neurology. 2000; 54: 2261-2268
        • Winblad B
        • Wimo A
        • Engedal K
        • et al.
        3-Year study of donepezil therapy in Alzheimer's disease: Effects of early and continuous therapy.
        Dement Geriatr Cogn Disord. 2006; 21: 353-363
      1. (Available at)
        • Thomson American Health Consultants
        Alzheimer's disease: Risk stratification, patient evaluation, and outcome-effective pharmacologic therapy—year 2004 clinical update. Recommendations and treatment guidelines of the Alzheimer's Disease Management Council (ADMC) Clinical Consensus Panel.
        (Accessed December 15, 2005)
        • Van Der Flier WM
        • Van Den Heuvel DM
        • Weverling-Rijnsburger AW
        • et al.
        Cognitive decline in AD and mild cognitive impairment is associated with global brain damage.
        Neurology. 2002; 59: 874-879
        • Jack Jr, CR
        • Petersen RC
        • Xu YC
        • et al.
        Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease.
        Neurology. 1997; 49: 786-794
        • Grundman M
        • Petersen RC
        • Ferris SH
        • Alzheimer's Disease Cooperative Study
        • et al.
        Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials.
        Arch Neurol. 2004; 61: 59-66
        • Jack Jr, CR
        • Petersen RC
        • Xu Y
        • et al.
        Rates of hippocampal atrophy correlate with change in clinical status in aging and AD.
        Neurology. 2000; 55: 484-489
        • Rusinek H
        • De Santi S
        • Frid D
        • et al.
        Regional brain atrophy rate predicts future cognitive decline: 6-Year longitudinal MR imaging study of normal aging.
        Radiology. 2003; 229: 691-696
        • Squire LR
        Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans.
        Psychol Rev. 1992; 99 ([published correction appears in Psychol Rev. 1992;99:582]): 195-231
        • Fellgiebel A
        • Wille P
        • Muller MJ
        • et al.
        Ultrastructural hippocampal and white matter alterations in mild cognitive impairment: A diffusion tensor imaging study.
        Dement Geriatr Cogn Disord. 2004; 18: 101-108
        • de Leon MJ
        • DeSanti S
        • Zinkowski R
        • et al.
        MRI and CSF studies in the early diagnosis of Alzheimer's disease.
        J Intern Med. 2004; 256: 205-223
        • Klunk WE
        • Engler H
        • Nordberg A
        • et al.
        Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
        Ann Neurol. 2004; 55: 306-319
        • Small GW
        • Kepe V
        • Huang SC
        • et al.
        Plaque and tangle brain imaging using [F-18]FDDNP-pet differentiates Alzheimer's disease, mild cognitive impairment, and older controls.
        Neurobiol Aging. 2004; 25 (Abstract): S58
        • Saxton J
        • Lopez OL
        • Ratcliff G
        • et al.
        Preclinical Alzheimer disease: Neuropsychological test performance 1.5 to 8 years prior to onset.
        Neurology. 2004; 63: 2341-2347
        • Nordberg A
        Toward an early diagnosis and treatment of Alzheimer's disease.
        Int Psychogeriatr. 2003; 15: 223-237
        • Blennow K
        CSF biomarkers for mild cognitive impairment.
        J Intern Med. 2004; 256: 224-234
        • Buerger K
        • Teipel SJ
        • Zinkowski R
        • et al.
        CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects.
        Neurology. 2002; 59 ([published correction appears in Neurology. 2004;63:1144]): 627-629
        • Herukka SK
        • Hallikainen M
        • Soininen H
        • Pirttila T
        CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment.
        Neurology. 2005; 64: 1294-1297
        • Jack Jr, CR
        • Petersen RC
        • Xu YC
        • et al.
        Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment.
        Neurology. 1999; 52: 1397-1403
        • Mosconi L
        • Perani D
        • Sorbi S
        • et al.
        MCI conversion to dementia and the APOE genotype: A prediction study with FDG-PET.
        Neurology. 2004; 63: 2332-2340
        • Chetelat G
        • Desgranges B
        • de la Sayette V
        • et al.
        Mild cognitive impairment: Can FDG-PET predict who is to rapidly convert to Alzheimer's disease?.
        Neurology. 2003; 60: 1374-1377
        • Petersen RC
        • Smith GE
        • Ivnik RJ
        • et al.
        Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals.
        JAMA. 1995; 273 ([published correction appears in JAMA. 1995;274:538]): 1274-1278
        • Winblad B
        • Palmer K
        • Kivipelto M
        • et al.
        Mild cognitive impairment-beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment.
        J Intern Med. 2004; 256: 240-246
        • Tierney MC
        • Szalai JP
        • Snow WG
        • et al.
        A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment.
        Neurology. 1996; 46: 149-154
        • Folstein MF
        • Folstein SE
        • McHugh PR
        “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Benson AD
        • Slavin MJ
        • Tran TT
        • et al.
        Screening for early Alzheimer's disease: Is there still a role for the Mini-Mental State Examination?.
        Prim Care Companion J Clin Psychiatry. 2005; 7: 62-69
        • Nasreddine ZS
        • Phillips NA
        • Bedirian V
        • et al.
        The Montreal Cognitive Assessment, MoCA: A brief screening tool for mild cognitive impairment.
        J Am Geriatr Soc. 2005; 53: 695-699
        • Tornatore JB
        • Hill E
        • Laboff JA
        • McGann ME
        Self-administered screening for mild cognitive impairment: Initial validation of a computerized test battery.
        J Neuropsychiatry Clin Neurosci. 2005; 17: 98-105
        • Borson S
        • Scanlan JM
        • Chen P
        • Ganguli M
        The Mini-Cog as a screen for dementia: Validation in a population-based sample.
        J Am Geriatr Soc. 2003; 51: 1451-1454
        • Borson S
        • Scanlan JM
        • Watanabe J
        • et al.
        Simplifying detection of cognitive impairment: Comparison of the Mini-Cog and Mini-Mental State Examination in a multiethnic sample.
        J Am Geriatr Soc. 2005; 53: 871-874
        • Lyketsos CG
        • Lopez O
        • Jones B
        • et al.
        Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: Results from the Cardiovascular Health Study.
        JAMA. 2002; 288: 1475-1483
        • Carr DB
        • Gray S
        • Baty J
        • Morris JC
        The value of informant versus individual's complaints of memory impairment in early dementia.
        Neurology. 2000; 55: 1724-1726
        • Ganguli M
        • Burmeister LA
        • Seaberg EC
        • et al.
        Association between dementia and elevated TSH: A community-based study.
        Biol Psychiatry. 1996; 40: 714-725
        • Atti AR
        • Palmer K
        • Volpato S
        • et al.
        Anaemia increases the risk of dementia in cognitively intact elderly.
        Neurobiol Aging. 2006; 27: 278-284
        • Ohayon MM
        • Vecchierini MF
        Daytime sleepiness and cognitive impairment in the elderly population.
        Arch Intern Med. 2002; 162: 201-208
        • Gregg EW
        • Yaffe K
        • Cauley JA
        • et al.
        • Study of Osteoporotic Fractures Research Group
        Is diabetes associated with cognitive impairment and cognitive decline among older women?.
        Arch Intern Med. 2000; 160: 174-180
        • Kivipelto M
        • Helkala EL
        • Hanninen T
        • et al.
        Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study.
        Neurology. 2001; 56: 1683-1689
        • Tzourio C
        • Dufouil C
        • Ducimetiere P
        • Alperovitch A
        • EVA Study Group (Epidemiology of Vascular Aging)
        Cognitive decline in individuals with high blood pressure: A longitudinal study in the elderly.
        Neurology. 1999; 53: 1948-1952
        • Geerlings MI
        • Schoevers RA
        • Beekman AT
        • et al.
        Depression and risk of cognitive decline and Alzheimer's disease. Results of two prospective community-based studies in The Netherlands.
        Br J Psychiatry. 2000; 176: 568-575
        • Kado DM
        • Karlamangla AS
        • Huang MH
        • et al.
        Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging.
        Am J Med. 2005; 118: 161-167
        • O'Brien JT
        • Erkinjuntti T
        • Reisberg B
        • et al.
        Vascular cognitive impairment.
        Lancet Neurol. 2003; 2: 89-98
        • Mecocci P
        • Mariani E
        • Cornacchiola V
        • Polidori MC
        Antioxidants for the treatment of mild cognitive impairment.
        Neurol Res. 2004; 26: 598-602
        • Le Bars PL
        • Katz MM
        • Berman N
        • et al.
        • North American EGb Study Group
        A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia.
        JAMA. 1997; 278: 1327-1332
        • Sano M
        • Ernesto C
        • Thomas RG
        • et al.
        A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study.
        N Engl J Med. 1997; 336: 1216-1222
        • Mulnard RA
        • Corrada MM
        • Kawas CH
        Estrogen replacement therapy, Alzheimer's disease, and mild cognitive impairment.
        Curr Neurol Neurosci Rep. 2004; 4: 368-373
        • Espeland MA
        • Rapp SR
        • Shumaker SA
        • Women's Health Initiative Memory Study
        • et al.
        Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study.
        JAMA. 2004; 291: 2959-2968
        • Rapp SR
        • Espeland MA
        • Shumaker SA
        • WHIMS Investigators
        • et al.
        Effect of estrogen plus progestin on global cognitive function in postmenopausal women: The Women's Health Initiative Memory Study: A randomized controlled trial.
        JAMA. 2003; 289: 2663-2672
        • Shumaker SA
        • Legault C
        • Kuller L
        • Women's Health Initiative Memory Study
        • et al.
        Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study.
        JAMA. 2004; 291: 2947-2958
        • Thal LJ
        • Ferris SH
        • Kirby L
        • et al.
        • Rofecoxib Protocol 078 Study Group
        A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment.
        Neuropsychopharmacology. 2005; 30: 1204-1215
        • Salloway S
        • Ferris S
        • Kluger A
        • et al.
        • Donepezil 401 Study Group
        Efficacy of donepezil in mild cognitive impairment: A randomized placebo-controlled trial.
        Neurology. 2004; 63: 651-657
        • Koontz J
        • Baskys A
        Effects of galantamine on working memory and global functioning in patients with mild cognitive impairment: A double-blind placebo-controlled study.
        Am J Alzheimers Dis Other Demen. 2005; 20: 295-302
        • Loy C
        • Schneider L
        Galantamine for Alzheimer's disease and mild cognitive impairment.
        Cochrane Database Syst Rev. 2006; 1: CD001747
      2. (Available at)
        • Waknine Y
        FDA cautions against use of Reminyl for mild cognitive impairment.
        (Accessed March 16 2006)
      3. (Available at)
        Investigation into delay to diagnosis of Alzheimer's disease with Exelon (InDDEx).
        (Accessed March 16 2006)
      4. (Available at)
        Treatment for early memory loss.
        (Accessed March 16 2006)
        • Suh YH
        • Checler F
        Amyloid precursor protein, presenilins, and alpha-synuclein: Molecular pathogenesis and pharmacological applications in Alzheimer's disease.
        Pharmacol Rev. 2002; 54: 469-525