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Mild cognitive impairment: Prognosis and treatment

Authors
Eric M McDade, DO
Ronald C Petersen, MD, PhD
Section Editor
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor
April F Eichler, MD, MPH

INTRODUCTION

Mild cognitive impairment (MCI) is an intermediate state between normal cognition and dementia. While specific changes in cognition are frequently observed in normal aging, there is increasing evidence that some forms of cognitive impairment are recognizable as an early manifestation of dementia [1]. The utility of this paradigm centers around the recognition that dementia is not a dichotomous state. Our understanding of transitional states between normal cognition and dementia will improve the understanding of cognitive decline, facilitate early diagnosis, and ultimately benefit patients.

This topic will review the prognosis and treatment of MCI. The epidemiology, pathology, and clinical assessment of MCI and topics related to dementia, including diagnosis, treatment, risk factors, and prevention of dementia, are discussed separately. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment" and "Treatment of dementia" and "Risk factors for cognitive decline and dementia" and "Prevention of dementia" and "Clinical features and diagnosis of Alzheimer disease".)

PROGRESSION TO DEMENTIA

It is generally accepted that older adults with mild cognitive impairment (MCI) are at increased risk of developing Alzheimer disease (AD) [1-3].

In a prospective study of 798 older Catholic clergy without dementia, participants were categorized at baseline as having MCI (n = 211) or no cognitive impairment (n = 587) and were followed for an average of 4.5 years with cognitive tests [1]. The group with MCI developed AD at a rate 3.1 (CI 2.1-4.5) times higher than the group with no cognitive impairment. Another study found that MCI was associated with a 2.8-fold increased risk of AD [2]. In the Mayo Clinic Study of Aging, the risk of dementia was increased 23-fold in adults with MCI compared with cognitively normal subjects over five years of follow up [3].

In various studies, a substantial percentage (11 to 40 percent) of patients with MCI improve, even to normal, over a one to three-year follow-up time [4-9]. This finding emphasizes the clinical heterogeneity of MCI. However, such patients remains at significantly increased risk for a future diagnosis of dementia compared with those who have never received a diagnosis of MCI [3,9,10].

                           

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Literature review current through: Nov 2016. | This topic last updated: Wed May 04 00:00:00 GMT 2016.
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References
Top
  1. Bennett DA, Wilson RS, Schneider JA, et al. Natural history of mild cognitive impairment in older persons. Neurology 2002; 59:198.
  2. Manly JJ, Tang MX, Schupf N, et al. Frequency and course of mild cognitive impairment in a multiethnic community. Ann Neurol 2008; 63:494.
  3. Roberts RO, Knopman DS, Mielke MM, et al. Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 2014; 82:317.
  4. Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 2001; 56:37.
  5. Ganguli M, Dodge HH, Shen C, DeKosky ST. Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology 2004; 63:115.
  6. Larrieu S, Letenneur L, Orgogozo JM, et al. Incidence and outcome of mild cognitive impairment in a population-based prospective cohort. Neurology 2002; 59:1594.
  7. Palmer K, Wang HX, Bäckman L, et al. Differential evolution of cognitive impairment in nondemented older persons: results from the Kungsholmen Project. Am J Psychiatry 2002; 159:436.
  8. Wahlund LO, Pihlstrand E, Jönhagen ME. Mild cognitive impairment: experience from a memory clinic. Acta Neurol Scand Suppl 2003; 179:21.
  9. Koepsell TD, Monsell SE. Reversion from mild cognitive impairment to normal or near-normal cognition: risk factors and prognosis. Neurology 2012; 79:1591.
  10. Lopez OL, Becker JT, Chang YF, et al. Incidence of mild cognitive impairment in the Pittsburgh Cardiovascular Health Study-Cognition Study. Neurology 2012; 79:1599.
  11. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303.
  12. Boyle PA, Wilson RS, Aggarwal NT, et al. Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline. Neurology 2006; 67:441.
  13. Busse A, Hensel A, Gühne U, et al. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology 2006; 67:2176.
  14. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med 2008; 148:427.
  15. Tschanz JT, Welsh-Bohmer KA, Lyketsos CG, et al. Conversion to dementia from mild cognitive disorder: the Cache County Study. Neurology 2006; 67:229.
  16. Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005; 352:2379.
  17. Hansson O, Zetterberg H, Buchhave P, et al. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5:228.
  18. Visser PJ, Kester A, Jolles J, Verhey F. Ten-year risk of dementia in subjects with mild cognitive impairment. Neurology 2006; 67:1201.
  19. Fischer P, Jungwirth S, Zehetmayer S, et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 2007; 68:288.
  20. Lopez OL, Kuller LH, Becker JT, et al. Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study. Arch Neurol 2007; 64:416.
  21. Farias ST, Mungas D, Reed BR, et al. Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol 2009; 66:1151.
  22. Mitchell AJ, Shiri-Feshki M. Temporal trends in the long term risk of progression of mild cognitive impairment: a pooled analysis. J Neurol Neurosurg Psychiatry 2008; 79:1386.
  23. Stokholm J, Jakobsen O, Czarna JM, et al. Years of severe and isolated amnesia can precede the development of dementia in early-onset Alzheimer's disease. Neurocase 2005; 11:48.
  24. Heister D, Brewer JB, Magda S, et al. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology 2011; 77:1619.
  25. DeCarli C, Mungas D, Harvey D, et al. Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 2004; 63:220.
  26. Kryscio RJ, Schmitt FA, Salazar JC, et al. Risk factors for transitions from normal to mild cognitive impairment and dementia. Neurology 2006; 66:828.
  27. Tyas SL, Salazar JC, Snowdon DA, et al. Transitions to mild cognitive impairments, dementia, and death: findings from the Nun Study. Am J Epidemiol 2007; 165:1231.
  28. Amieva H, Letenneur L, Dartigues JF, et al. Annual rate and predictors of conversion to dementia in subjects presenting mild cognitive impairment criteria defined according to a population-based study. Dement Geriatr Cogn Disord 2004; 18:87.
  29. Buerger K, Teipel SJ, Zinkowski R, et al. CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology 2002; 59:627.
  30. Peltz CB, Corrada MM, Berlau DJ, Kawas CH. Incidence of dementia in oldest-old with amnestic MCI and other cognitive impairments. Neurology 2011; 77:1906.
  31. Saxton J, Snitz BE, Lopez OL, et al. Functional and cognitive criteria produce different rates of mild cognitive impairment and conversion to dementia. J Neurol Neurosurg Psychiatry 2009; 80:737.
  32. Amieva H, Jacqmin-Gadda H, Orgogozo JM, et al. The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain 2005; 128:1093.
  33. Fleisher AS, Sowell BB, Taylor C, et al. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 2007; 68:1588.
  34. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001; 58:397.
  35. Sacuiu S, Sjögren M, Johansson B, et al. Prodromal cognitive signs of dementia in 85-year-olds using four sources of information. Neurology 2005; 65:1894.
  36. Laukka EJ, MacDonald SW, Bäckman L. Contrasting cognitive trajectories of impending death and preclinical dementia in the very old. Neurology 2006; 66:833.
  37. Nordlund A, Rolstad S, Klang O, et al. Two-year outcome of MCI subtypes and aetiologies in the Göteborg MCI study. J Neurol Neurosurg Psychiatry 2010; 81:541.
  38. Ganguli M, Snitz BE, Saxton JA, et al. Outcomes of mild cognitive impairment by definition: a population study. Arch Neurol 2011; 68:761.
  39. Chang YL, Bondi MW, McEvoy LK, et al. Global clinical dementia rating of 0.5 in MCI masks variability related to level of function. Neurology 2011; 76:652.
  40. Tobiansky R, Blizard R, Livingston G, Mann A. The Gospel Oak Study stage IV: the clinical relevance of subjective memory impairment in older people. Psychol Med 1995; 25:779.
  41. Geerlings MI, Jonker C, Bouter LM, et al. Association between memory complaints and incident Alzheimer's disease in elderly people with normal baseline cognition. Am J Psychiatry 1999; 156:531.
  42. van Norden AG, Fick WF, de Laat KF, et al. Subjective cognitive failures and hippocampal volume in elderly with white matter lesions. Neurology 2008; 71:1152.
  43. Scheef L, Spottke A, Daerr M, et al. Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment. Neurology 2012; 79:1332.
  44. Barbeau E, Didic M, Tramoni E, et al. Evaluation of visual recognition memory in MCI patients. Neurology 2004; 62:1317.
  45. Tierney MC, Yao C, Kiss A, McDowell I. Neuropsychological tests accurately predict incident Alzheimer disease after 5 and 10 years. Neurology 2005; 64:1853.
  46. Riemenschneider M, Lautenschlager N, Wagenpfeil S, et al. Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Arch Neurol 2002; 59:1729.
  47. Chen P, Ratcliff G, Belle SH, et al. Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 2000; 55:1847.
  48. Aggarwal NT, Wilson RS, Beck TL, et al. Mild cognitive impairment in different functional domains and incident Alzheimer's disease. J Neurol Neurosurg Psychiatry 2005; 76:1479.
  49. Pérès K, Chrysostome V, Fabrigoule C, et al. Restriction in complex activities of daily living in MCI: impact on outcome. Neurology 2006; 67:461.
  50. Sarazin M, Berr C, De Rotrou J, et al. Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study. Neurology 2007; 69:1859.
  51. Dickerson BC, Sperling RA, Hyman BT, et al. Clinical prediction of Alzheimer disease dementia across the spectrum of mild cognitive impairment. Arch Gen Psychiatry 2007; 64:1443.
  52. Fleisher AS, Sun S, Taylor C, et al. Volumetric MRI vs clinical predictors of Alzheimer disease in mild cognitive impairment. Neurology 2008; 70:191.
  53. Storandt M, Grant EA, Miller JP, Morris JC. Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI. Neurology 2006; 67:467.
  54. Touchon J, Ritchie K. Prodromal cognitive disorder in Alzheimer's disease. Int J Geriatr Psychiatry 1999; 14:556.
  55. Wilson RS, Leurgans SE, Boyle PA, Bennett DA. Cognitive decline in prodromal Alzheimer disease and mild cognitive impairment. Arch Neurol 2011; 68:351.
  56. Ivnik RJ, Smith GE, Lucas JA, et al. Testing normal older people three or four times at 1- to 2-year intervals: defining normal variance. Neuropsychology 1999; 13:121.
  57. Machulda MM, Pankratz VS, Christianson TJ, et al. Practice effects and longitudinal cognitive change in normal aging vs. incident mild cognitive impairment and dementia in the Mayo Clinic Study of Aging. Clin Neuropsychol 2013; 27:1247.
  58. Palmer K, Berger AK, Monastero R, et al. Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology 2007; 68:1596.
  59. Teng E, Lu PH, Cummings JL. Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer's disease. Dement Geriatr Cogn Disord 2007; 24:253.
  60. Goveas JS, Espeland MA, Woods NF, et al. Depressive symptoms and incidence of mild cognitive impairment and probable dementia in elderly women: the Women's Health Initiative Memory Study. J Am Geriatr Soc 2011; 59:57.
  61. Caracciolo B, Bäckman L, Monastero R, et al. The symptom of low mood in the prodromal stage of mild cognitive impairment and dementia: a cohort study of a community dwelling elderly population. J Neurol Neurosurg Psychiatry 2011; 82:788.
  62. Ramakers IH, Visser PJ, Aalten P, et al. Affective symptoms as predictors of Alzheimer's disease in subjects with mild cognitive impairment: a 10-year follow-up study. Psychol Med 2010; 40:1193.
  63. Vicini Chilovi B, Conti M, Zanetti M, et al. Differential impact of apathy and depression in the development of dementia in mild cognitive impairment patients. Dement Geriatr Cogn Disord 2009; 27:390.
  64. Panza F, Capurso C, D'Introno A, et al. Impact of depressive symptoms on the rate of progression to dementia in patients affected by mild cognitive impairment. The Italian Longitudinal Study on Aging. Int J Geriatr Psychiatry 2008; 23:726.
  65. Verghese J, Wang C, Lipton RB, Holtzer R. Motoric cognitive risk syndrome and the risk of dementia. J Gerontol A Biol Sci Med Sci 2013; 68:412.
  66. Verghese J, Annweiler C, Ayers E, et al. Motoric cognitive risk syndrome: multicountry prevalence and dementia risk. Neurology 2014; 83:718.
  67. Roberts RO, Christianson TJ, Kremers WK, et al. Association Between Olfactory Dysfunction and Amnestic Mild Cognitive Impairment and Alzheimer Disease Dementia. JAMA Neurol 2016; 73:93.
  68. Wilson RS, Schneider JA, Arnold SE, et al. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007; 64:802.
  69. Devanand DP, Lee S, Manly J, et al. Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community. Neurology 2015; 84:182.
  70. Devanand DP, Michaels-Marston KS, Liu X, et al. Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow-up. Am J Psychiatry 2000; 157:1399.
  71. Tabert MH, Liu X, Doty RL, et al. A 10-item smell identification scale related to risk for Alzheimer's disease. Ann Neurol 2005; 58:155.
  72. 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; 273:1274.
  73. Li J, Wang YJ, Zhang M, et al. Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 2011; 76:1485.
  74. Wang PN, Hong CJ, Lin KN, et al. APOE ε4 increases the risk of progression from amnestic mild cognitive impairment to Alzheimer's disease among ethnic Chinese in Taiwan. J Neurol Neurosurg Psychiatry 2011; 82:165.
  75. Boyle PA, Buchman AS, Wilson RS, et al. The APOE epsilon4 allele is associated with incident mild cognitive impairment among community-dwelling older persons. Neuroepidemiology 2010; 34:43.
  76. Devanand DP, Pelton GH, Zamora D, et al. Predictive utility of apolipoprotein E genotype for Alzheimer disease in outpatients with mild cognitive impairment. Arch Neurol 2005; 62:975.
  77. Aggarwal NT, Wilson RS, Beck TL, et al. The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment. Neurocase 2005; 11:3.
  78. Killiany RJ, Gomez-Isla T, Moss M, et al. Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol 2000; 47:430.
  79. Elias-Sonnenschein LS, Viechtbauer W, Ramakers IH, et al. Predictive value of APOE-ε4 allele for progression from MCI to AD-type dementia: a meta-analysis. J Neurol Neurosurg Psychiatry 2011; 82:1149.
  80. Ng TP, Feng L, Nyunt MS, et al. Metabolic Syndrome and the Risk of Mild Cognitive Impairment and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort. JAMA Neurol 2016; 73:456.
  81. Solfrizzi V, Panza F, Colacicco AM, et al. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology 2004; 63:1882.
  82. Di Carlo A, Lamassa M, Baldereschi M, et al. CIND and MCI in the Italian elderly: frequency, vascular risk factors, progression to dementia. Neurology 2007; 68:1909.
  83. Simonsen AH, McGuire J, Hansson O, et al. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol 2007; 64:366.
  84. Maruyama M, Matsui T, Tanji H, et al. Cerebrospinal fluid tau protein and periventricular white matter lesions in patients with mild cognitive impairment: implications for 2 major pathways. Arch Neurol 2004; 61:716.
  85. Buerger K, Ewers M, Andreasen N, et al. Phosphorylated tau predicts rate of cognitive decline in MCI subjects: a comparative CSF study. Neurology 2005; 65:1502.
  86. Ewers M, Buerger K, Teipel SJ, et al. Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 2007; 69:2205.
  87. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009; 302:385.
  88. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: diagnostic discrimination and cognitive correlations. Neurology 2009; 73:287.
  89. Vemuri P, Wiste HJ, Weigand SD, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology 2009; 73:294.
  90. Mitchell AJ. CSF phosphorylated tau in the diagnosis and prognosis of mild cognitive impairment and Alzheimer's disease: a meta-analysis of 51 studies. J Neurol Neurosurg Psychiatry 2009; 80:966.
  91. De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people. Arch Neurol 2010; 67:949.
  92. van Rossum IA, Vos SJ, Burns L, et al. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology 2012; 79:1809.
  93. Skoog I, Davidsson P, Aevarsson O, et al. Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement Geriatr Cogn Disord 2003; 15:169.
  94. Moonis M, Swearer JM, Dayaw MP, et al. Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology 2005; 65:323.
  95. Graff-Radford NR, Crook JE, Lucas J, et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 2007; 64:354.
  96. Li G, Sokal I, Quinn JF, et al. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology 2007; 69:631.
  97. Fagan AM, Head D, Shah AR, et al. Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 2009; 65:176.
  98. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 2009; 65:403.
  99. Snider BJ, Fagan AM, Roe C, et al. Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Arch Neurol 2009; 66:638.
  100. Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 2009; 8:619.
  101. Petersen RC, Aisen PS, Beckett LA, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology 2010; 74:201.
  102. Landau SM, Harvey D, Madison CM, et al. Comparing predictors of conversion and decline in mild cognitive impairment. Neurology 2010; 75:230.
  103. Seppälä TT, Herukka SK, Hänninen T, et al. Plasma Abeta42 and Abeta40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study. J Neurol Neurosurg Psychiatry 2010; 81:1123.
  104. Lo RY, Hubbard AE, Shaw LM, et al. Longitudinal change of biomarkers in cognitive decline. Arch Neurol 2011; 68:1257.
  105. Vemuri P, Wiste HJ, Weigand SD, et al. Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology 2010; 75:143.
  106. Ritchie C, Smailagic N, Noel-Storr AH, et al. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2014; :CD008782.
  107. Britschgi M, Wyss-Coray T. Blood protein signature for the early diagnosis of Alzheimer disease. Arch Neurol 2009; 66:161.
  108. Ray S, Britschgi M, Herbert C, et al. Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med 2007; 13:1359.
  109. O'Bryant SE, Xiao G, Barber R, et al. A serum protein-based algorithm for the detection of Alzheimer disease. Arch Neurol 2010; 67:1077.
  110. van de Pol LA, Korf ES, van der Flier WM, et al. Magnetic resonance imaging predictors of cognition in mild cognitive impairment. Arch Neurol 2007; 64:1023.
  111. Fox NC, Crum WR, Scahill RI, et al. Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images. Lancet 2001; 358:201.
  112. Smith EE, Egorova S, Blacker D, et al. Magnetic resonance imaging white matter hyperintensities and brain volume in the prediction of mild cognitive impairment and dementia. Arch Neurol 2008; 65:94.
  113. Becker JT, Davis SW, Hayashi KM, et al. Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment. Arch Neurol 2006; 63:97.
  114. Stewart R, Dufouil C, Godin O, et al. Neuroimaging correlates of subjective memory deficits in a community population. Neurology 2008; 70:1601.
  115. Zimmerman ME, Pan JW, Hetherington HP, et al. Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults. Neurology 2008; 70:1594.
  116. Korf ES, Wahlund LO, Visser PJ, Scheltens P. Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 2004; 63:94.
  117. Geroldi C, Rossi R, Calvagna C, et al. Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment. J Neurol Neurosurg Psychiatry 2006; 77:1219.
  118. DeCarli C, Frisoni GB, Clark CM, et al. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol 2007; 64:108.
  119. Jack CR Jr, Bernstein MA, Fox NC, et al. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging 2008; 27:685.
  120. Stoub TR, Bulgakova M, Leurgans S, et al. MRI predictors of risk of incident Alzheimer disease: a longitudinal study. Neurology 2005; 64:1520.
  121. Mungas D, Harvey D, Reed BR, et al. Longitudinal volumetric MRI change and rate of cognitive decline. Neurology 2005; 65:565.
  122. Jack CR Jr, Shiung MM, Weigand SD, et al. Brain atrophy rates predict subsequent clinical conversion in normal elderly and amnestic MCI. Neurology 2005; 65:1227.
  123. Bell-McGinty S, Lopez OL, Meltzer CC, et al. Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 2005; 62:1393.
  124. Erten-Lyons D, Howieson D, Moore MM, et al. Brain volume loss in MCI predicts dementia. Neurology 2006; 66:233.
  125. Apostolova LG, Dutton RA, Dinov ID, et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol 2006; 63:693.
  126. Devanand DP, Pradhaban G, Liu X, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology 2007; 68:828.
  127. Whitwell JL, Shiung MM, Przybelski SA, et al. MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology 2008; 70:512.
  128. Jack CR Jr, Weigand SD, Shiung MM, et al. Atrophy rates accelerate in amnestic mild cognitive impairment. Neurology 2008; 70:1740.
  129. Desikan RS, Fischl B, Cabral HJ, et al. MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD. Neurology 2008; 71:819.
  130. Duara R, Loewenstein DA, Potter E, et al. Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease. Neurology 2008; 71:1986.
  131. McEvoy LK, Fennema-Notestine C, Roddey JC, et al. Alzheimer disease: quantitative structural neuroimaging for detection and prediction of clinical and structural changes in mild cognitive impairment. Radiology 2009; 251:195.
  132. Henneman WJ, Sluimer JD, Barnes J, et al. Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology 2009; 72:999.
  133. Davatzikos C, Xu F, An Y, et al. Longitudinal progression of Alzheimer's-like patterns of atrophy in normal older adults: the SPARE-AD index. Brain 2009; 132:2026.
  134. Desikan RS, Cabral HJ, Hess CP, et al. Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease. Brain 2009; 132:2048.
  135. den Heijer T, van der Lijn F, Koudstaal PJ, et al. A 10-year follow-up of hippocampal volume on magnetic resonance imaging in early dementia and cognitive decline. Brain 2010; 133:1163.
  136. Verdelho A, Madureira S, Moleiro C, et al. White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study. Neurology 2010; 75:160.
  137. Koivunen J, Scheinin N, Virta JR, et al. Amyloid PET imaging in patients with mild cognitive impairment: a 2-year follow-up study. Neurology 2011; 76:1085.
  138. Kantarci K, Petersen RC, Boeve BF, et al. DWI predicts future progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology 2005; 64:902.
  139. Ray KM, Wang H, Chu Y, et al. Mild cognitive impairment: apparent diffusion coefficient in regional gray matter and white matter structures. Radiology 2006; 241:197.
  140. van de Pol LA, van der Flier WM, Korf ES, et al. Baseline predictors of rates of hippocampal atrophy in mild cognitive impairment. Neurology 2007; 69:1491.
  141. Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology 2009; 72:1048.
  142. Querbes O, Aubry F, Pariente J, et al. Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve. Brain 2009; 132:2036.
  143. Jack CR Jr, Lowe VJ, Senjem ML, et al. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain 2008; 131:665.
  144. Holland D, Brewer JB, Hagler DJ, et al. Subregional neuroanatomical change as a biomarker for Alzheimer's disease. Proc Natl Acad Sci U S A 2009; 106:20954.
  145. Jack CR Jr, Lowe VJ, Weigand SD, et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease. Brain 2009; 132:1355.
  146. DeCarli C, Miller BL, Swan GE, et al. Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch Neurol 2001; 58:643.
  147. Bombois S, Debette S, Delbeuck X, et al. Prevalence of subcortical vascular lesions and association with executive function in mild cognitive impairment subtypes. Stroke 2007; 38:2595.
  148. Debette S, Bombois S, Bruandet A, et al. Subcortical hyperintensities are associated with cognitive decline in patients with mild cognitive impairment. Stroke 2007; 38:2924.
  149. Kantarci K, Weigand SD, Przybelski SA, et al. Risk of dementia in MCI: combined effect of cerebrovascular disease, volumetric MRI, and 1H MRS. Neurology 2009; 72:1519.
  150. Luchsinger JA, Brickman AM, Reitz C, et al. Subclinical cerebrovascular disease in mild cognitive impairment. Neurology 2009; 73:450.
  151. Debette S, Beiser A, DeCarli C, et al. Association of MRI markers of vascular brain injury with incident stroke, mild cognitive impairment, dementia, and mortality: the Framingham Offspring Study. Stroke 2010; 41:600.
  152. Silbert LC, Dodge HH, Perkins LG, et al. Trajectory of white matter hyperintensity burden preceding mild cognitive impairment. Neurology 2012; 79:741.
  153. Staekenborg SS, Koedam EL, Henneman WJ, et al. Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy. Stroke 2009; 40:1269.
  154. Bombois S, Debette S, Bruandet A, et al. Vascular subcortical hyperintensities predict conversion to vascular and mixed dementia in MCI patients. Stroke 2008; 39:2046.
  155. Lopez OL, Klunk WE, Mathis C, et al. Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old. Neurology 2014; 83:1804.
  156. Caroli A, Prestia A, Galluzzi S, et al. Mild cognitive impairment with suspected nonamyloid pathology (SNAP): Prediction of progression. Neurology 2015; 84:508.
  157. 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.
  158. Chételat 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.
  159. Anchisi D, Borroni B, Franceschi M, et al. Heterogeneity of brain glucose metabolism in mild cognitive impairment and clinical progression to Alzheimer disease. Arch Neurol 2005; 62:1728.
  160. Jagust W, Gitcho A, Sun F, et al. Brain imaging evidence of preclinical Alzheimer's disease in normal aging. Ann Neurol 2006; 59:673.
  161. Small GW, Kepe V, Ercoli LM, et al. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 2006; 355:2652.
  162. Caselli RJ, Chen K, Lee W, et al. Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Arch Neurol 2008; 65:1231.
  163. Fouquet M, Desgranges B, Landeau B, et al. Longitudinal brain metabolic changes from amnestic mild cognitive impairment to Alzheimer's disease. Brain 2009; 132:2058.
  164. Smailagic N, Vacante M, Hyde C, et al. ¹⁸F-FDG PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2015; 1:CD010632.
  165. Petersen RC. Does the source of subjects matter?: absolutely! Neurology 2010; 74:1754.
  166. Guedj E, Barbeau EJ, Didic M, et al. Identification of subgroups in amnestic mild cognitive impairment. Neurology 2006; 67:356.
  167. Johnson KA, Moran EK, Becker JA, et al. Single photon emission computed tomography perfusion differences in mild cognitive impairment. J Neurol Neurosurg Psychiatry 2007; 78:240.
  168. Miller SL, Fenstermacher E, Bates J, et al. Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. J Neurol Neurosurg Psychiatry 2008; 79:630.
  169. O'Brien JL, O'Keefe KM, LaViolette PS, et al. Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology 2010; 74:1969.
  170. Petrella JR, Sheldon FC, Prince SE, et al. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology 2011; 76:511.
  171. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015; 313:1924.
  172. Wolk DA, Price JC, Saxton JA, et al. Amyloid imaging in mild cognitive impairment subtypes. Ann Neurol 2009; 65:557.
  173. Okello A, Koivunen J, Edison P, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. Neurology 2009; 73:754.
  174. Forsberg A, Engler H, Almkvist O, et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008; 29:1456.
  175. Resnick SM, Sojkova J, Zhou Y, et al. Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB. Neurology 2010; 74:807.
  176. Small GW, Siddarth P, Kepe V, et al. Prediction of cognitive decline by positron emission tomography of brain amyloid and tau. Arch Neurol 2012; 69:215.
  177. Doraiswamy PM, Sperling RA, Coleman RE, et al. Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline: a multicenter study. Neurology 2012; 79:1636.
  178. Landau SM, Mintun MA, Joshi AD, et al. Amyloid deposition, hypometabolism, and longitudinal cognitive decline. Ann Neurol 2012; 72:578.
  179. Zhang S, Smailagic N, Hyde C, et al. (11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2014; :CD010386.
  180. Petersen RC, Aisen P, Boeve BF, et al. Mild cognitive impairment due to Alzheimer disease in the community. Ann Neurol 2013; 74:199.
  181. Sachs GA, Carter R, Holtz LR, et al. Cognitive impairment: an independent predictor of excess mortality: a cohort study. Ann Intern Med 2011; 155:300.
  182. Wilson RS, Aggarwal NT, Barnes LL, et al. Biracial population study of mortality in mild cognitive impairment and Alzheimer disease. Arch Neurol 2009; 66:767.
  183. Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev 2012; :CD009132.
  184. Cooper C, Li R, Lyketsos C, Livingston G. Treatment for mild cognitive impairment: systematic review. Br J Psychiatry 2013; 203:255.
  185. Tricco AC, Soobiah C, Berliner S, et al. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ 2013; 185:1393.
  186. Lu PH, Edland SD, Teng E, et al. Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology 2009; 72:2115.
  187. Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004; 63:651.
  188. Birks J, Flicker L. Donepezil for mild cognitive impairment. Cochrane Database Syst Rev 2006; :CD006104.
  189. Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology 2009; 72:1555.
  190. Winblad B, Gauthier S, Scinto L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008; 70:2024.
  191. Mayor S. Regulatory authorities review use of galantamine in mild cognitive impairment. BMJ 2005; 330:276.
  192. Feldman HH, Ferris S, Winblad B, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 2007; 6:501.
  193. Ströhle A, Schmidt DK, Schultz F, et al. Drug and Exercise Treatment of Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. Am J Geriatr Psychiatry 2015; 23:1234.
  194. Chertkow H, Massoud F, Nasreddine Z, et al. Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ 2008; 178:1273.
  195. Thal LJ, Ferris SH, Kirby L, et al. A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment. Neuropsychopharmacology 2005; 30:1204.
  196. DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008; 300:2253.
  197. Snitz BE, O'Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA 2009; 302:2663.
  198. Vellas B, Coley N, Ousset PJ, et al. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial. Lancet Neurol 2012; 11:851.
  199. Cunnane SC, Schneider JA, Tangney C, et al. Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis 2012; 29:691.
  200. Mulder C, Wahlund LO, Teerlink T, et al. Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer's disease. J Neural Transm (Vienna) 2003; 110:949.
  201. Trushina E, Dutta T, Persson XM, et al. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer's disease using metabolomics. PLoS One 2013; 8:e63644.
  202. Cenacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano) 1993; 5:123.
  203. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991; 41:644.
  204. Kato-Kataoka A, Sakai M, Ebina R, et al. Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints. J Clin Biochem Nutr 2010; 47:246.
  205. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev 2001; 122:2041.
  206. Jorissen BL, Brouns F, Van Boxtel MP, et al. The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment. Nutr Neurosci 2001; 4:121.
  207. Vakhapova V, Cohen T, Richter Y, et al. Phosphatidylserine containing omega-3 fatty acids may improve memory abilities in non-demented elderly with memory complaints: a double-blind placebo-controlled trial. Dement Geriatr Cogn Disord 2010; 29:467.
  208. Scholey AB, Camfield DA, Hughes ME, et al. A randomized controlled trial investigating the neurocognitive effects of Lacprodan® PL-20, a phospholipid-rich milk protein concentrate, in elderly participants with age-associated memory impairment: the Phospholipid Intervention for Cognitive Ageing Reversal (PLICAR): study protocol for a randomized controlled trial. Trials 2013; 14:404.
  209. Newhouse P, Kellar K, Aisen P, et al. Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial. Neurology 2012; 78:91.
  210. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69:29.
  211. Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 2013; 27:505.
  212. Baker LD, Barsness SM, Borson S, et al. Effects of growth hormone–releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults: results of a controlled trial. Arch Neurol 2012; 69:1420.
  213. Balk EM, Raman G, Tatsioni A, et al. Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med 2007; 167:21.
  214. Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA 2008; 300:1027.
  215. Nagamatsu LS, Handy TC, Hsu CL, et al. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med 2012; 172:666.
  216. van Uffelen JG, Chinapaw MJ, van Mechelen W, Hopman-Rock M. Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sports Med 2008; 42:344.
  217. Verhaeghen P, Marcoen A, Goossens L. Improving memory performance in the aged through mnemonic training: a meta-analytic study. Psychol Aging 1992; 7:242.
  218. Stuss DT, Robertson IH, Craik FI, et al. Cognitive rehabilitation in the elderly: a randomized trial to evaluate a new protocol. J Int Neuropsychol Soc 2007; 13:120.
  219. Troyer, AK. Improving memory, knowledge, satisfaction, and functioning via an education and intervention program for older adults. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2001; 8:256.
  220. Jean L, Bergeron ME, Thivierge S, Simard M. Cognitive intervention programs for individuals with mild cognitive impairment: systematic review of the literature. Am J Geriatr Psychiatry 2010; 18:281.
  221. Kinsella GJ, Mullaly E, Rand E, et al. Early intervention for mild cognitive impairment: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2009; 80:730.