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Original Contribution |

Mild Cognitive Impairment Can Be Distinguished From Alzheimer Disease and Normal Aging for Clinical Trials FREE

Michael Grundman, MD, MPH; Ronald C. Petersen, PhD, MD; Steven H. Ferris, PhD; Ronald G. Thomas, PhD; Paul S. Aisen, MD; David A. Bennett, MD; Norman L. Foster, MD; Clifford R. Jack, Jr, MD; Douglas R. Galasko, MD; Rachelle Doody, MD, PhD; Jeffrey Kaye, MD; Mary Sano, PhD; Richard Mohs, PhD; Serge Gauthier, MD; Hyun T. Kim, MS; Shelia Jin, MD, MPH; Arlan N. Schultz, MA; Kimberly Schafer, MS; Ruth Mulnard, RN, DNSc; Christopher H. van Dyck, MD; Jacobo Mintzer, MD; Edward Y. Zamrini, MD; Deborah Cahn-Weiner, PhD; Leon J. Thal, MD ; for the Alzheimer's Disease Cooperative Study
[+] Author Affiliations

From the Departments of Neurosciences (Drs Grundman, Thomas, Galasko, Jin, and Thal, Messrs Kim and Schultz, and Ms Schafer) and Family and Preventive Medicine (Dr Thomas), University of California, San Diego, La Jolla; Departments of Neurology (Dr Petersen) and Diagnostic Radiology (Dr Jack), Mayo Clinic and Foundation, Rochester, Minn; Department of Psychiatry, New York University School of Medicine, New York (Dr Ferris); Department of Neurology, Georgetown University, Washington, DC (Dr Aisen); Rush Alzheimer's Disease Center, Rush Presbyterian–St Luke's Medical Center, Chicago, Ill (Dr Bennett); Department of Neurology, University of Michigan, Ann Arbor (Dr Foster); Baylor College of Medicine Alzheimer's Disease Research Center, Houston, Tex (Dr Doody); Department of Neurology, Oregon Health & Science University and the Portland Veterans Affairs Medical Center, Portland (Dr Kaye); Department of Neurology, Columbia University, New York (Dr Sano); Lilly Research Laboratories, Eli Lilly & Co, Indianapolis, Ind (Dr Mohs); Alzheimer's Disease Research Unit at the McGill Centre for Studies in Aging, McGill University, Montreal, Quebec (Dr Gauthier); Brain Aging Research Unit, University of California, Irvine (Dr Mulnard); Department of Psychiatry, Yale University, New Haven, Conn (Dr van Dyck); Department of Psychiatry, Medical University of South Carolina, Charleston (Dr Mintzer); Department of Neurology, University of Alabama at Birmingham (Dr Zamrini); and Department of Psychiatry and Human Behavior, Brown University, Providence, RI (Dr Cahn-Weiner). Dr Doody has received research grants and honoraria from Eisai Inc and Pfizer Inc in the past.


Arch Neurol. 2004;61(1):59-66. doi:10.1001/archneur.61.1.59.
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Background  Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD.

Objective  To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial.

Design  Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial.

Setting  Memory disorder centers in the United States and Canada.

Patients  A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0.

Main Outcome Measures  Clinical, neuropsychologic, functional, neuroimaging, and genetic measures.

Results  Mean ± SD Alzheimer's Disease Assessment Scale–Cognitive Subscale scores were 5.6 ± 3.3 for controls, 11.3 ± 4.4 for patients with MCI, 18.0 ± 6.2 for the AD CDR 0.5 group, and 25.2 ± 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E ϵ4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD.

Conclusions  Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

Figures in this Article

Mild cognitive impairment (MCI) represents a transitional state between healthy aging and very mild Alzheimer disease (AD) and has become the focal point of much research activity.1 Although MCI can present with a variety of symptoms, when memory loss is the predominant symptom it is termed "amnestic MCI" and is frequently a prodromal state of AD.1,2 In this study, MCI refers to amnestic MCI. Patients with MCI have a memory impairment that is out of proportion to that expected for their age, yet they do not meet commonly accepted criteria for dementia or AD. Studies38 suggest that these individuals tend to progress to clinically probable AD at a rate of approximately 10% to 15% per year. The American Academy of Neurology, in a recent evidence-based practice parameter on dementia,6 recognized MCI as an important clinical condition to identify and monitor, since several potential treatments for the condition are under investigation.

There is no proven therapy for MCI. As MCI may represent a prodromal state to clinical AD, treatments proposed for AD, such as antioxidants and cholinesterase inhibitors, may be useful in MCI.911 The present study was designed to use the infrastructure of the Alzheimer's Disease Cooperative Study (ADCS), a National Institute on Aging consortium of AD research centers, to evaluate the potential treatment effects of vitamin E or donepezil on the rate at which patients with MCI progress to clinically probable AD during 3 years of follow-up. The diagnosis of MCI requires considerable clinical judgment; therefore, for this trial we developed operational criteria that could be implemented consistently across centers. We describe the cognitive and functional characteristics of the participants with MCI recruited to this trial. The primary question that this study addresses is whether these operational criteria successfully distinguish patients with MCI from controls and patients with mild AD on specific clinical, neuropsychologic, functional, neuroimaging, or genetic measures. This is the first study to compare performance on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog),12 a standard instrument used in AD trials, in large samples of patients with MCI, simultaneously recruited controls, and patients with AD. In addition, the neuropsychologic battery and functional assessments performed in this trial have not previously been reported in patients with MCI or compared with controls or patients with very mild AD.

PATIENTS WITH MCI

The 769 participants in this study were recruited from 69 ADCS sites in the United States and Canada. The ADCS launched a nationwide advertisement campaign targeting the elderly population in cities with participating sites. In addition, individual sites also advertised locally and identified potential participants. To be eligible for study treatment, all participants had to meet the operational criteria for MCI, including (1) memory complaint, corroborated by an informant; (2) abnormal memory function, documented by delayed recall of one paragraph from the Logical Memory II subtest of the Wechsler Memory Scale–Revised13 (cutoff scores: ≤8 for ≥16 years of education; ≤4 for 8 to 15 years of education; and ≤2 for 0 to 7 years of education [the maximum number of paragraph items possible to correctly recall is 25]); (3) normal general cognitive function, as determined by a clinician's judgment based on a structured interview with the patient and an informant (Clinical Dementia Rating [CDR]) and a Mini-Mental State Examination (MMSE) score greater than or equal to 2414 (the clinician also had access to the ADAS-Cog, but no cutoff score on the ADAS-Cog was required for trial entry); (4) no or minimal impairment in activities of daily living (ADLs), as determined by a clinical interview with the patient and informant; and (5) not sufficiently impaired, cognitively and functionally, to meet National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for AD,15 as judged by an experienced AD research clinician. In addition, patients had to be aged 55 to 90 years, be in good health with no significant cerebral vascular disease, have a modified Hachinski score less than or equal to 4,16 have a Hamilton Depression Rating Scale score less than or equal to 12,17 and undergo a computed tomographic or magnetic resonance imaging (MRI) brain scan within 12 months before screening without indication of infection, infarction, or focal lesions. Patients were required to have a global CDR of 0.5, with at least a 0.5 in the memory domain. All patients and their representatives signed a written consent form that had been approved by the local institutional review board of each participating site.

At study entry, participants were assessed using the MMSE; the ADAS-Cog; the global CDR and CDR sum of boxes, the ADCS MCI-ADL Scale, a modification of the ADCS-ADL Scale18 designed to increase sensitivity to impairments in instrumental activities that may occur in MCI; the Global Deterioration Scale19; and a neuropsychologic battery, which consisted of the New York University paragraph recall test,20 the Symbol Digit Modalities test,21 the category fluency test,22 a number cancellation test,12 the Boston Naming Test,23 the digits backwards test,24 the clock drawing test, and a maze tracing task.12

CONTROL SUBJECTS

Simultaneously with the development of this trial, cognitively normal, healthy elderly control subjects were recruited in a parallel study. One objective in recruiting this control group was to assess for differences between MCI and normal aging on the clinical and neuropsychologic measures used in the MCI trial. The controls received the same instruments as the patients with MCI.

Cognitively normal subjects were drawn from cohorts followed at participating ADCS sites. The control subjects underwent a standard medical evaluation and were judged to be in good health. Enrolled controls were required to have a CDR of 0, an MMSE score greater than or equal to 26, and a delayed paragraph recall score greater than 10 for those with 16 or more years of education, greater than 6 for those with 8 to 15 years of education, and greater than 4 for those with 0 to 7 years of education. The ADCS recruited and assessed 107 controls at 20 sites. Twenty percent of the controls (1 of every 5 controls enrolled) were required to be minorities.

PATIENTS WITH AD

To provide greater context for the cognitive and functional characteristics of patients with MCI, it was desirable to compare patients with MCI recruited for this trial with patients with AD recruited by the ADCS in a typical AD trial. We therefore included in these analyses patients recently recruited to an ADCS clinical trial.25 We included patients with AD who had a global CDR of 0.5 (very mild AD) or 1.0 (mild AD). Patients with AD were required to meet the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria for probable AD and to have an MMSE score between 13 and 26. Not all of the instruments used in the MCI trial could be compared with the AD group as only a subset of the instruments were included in the AD trial (ie, MMSE, ADAS-Cog, CDR, and Hachinski).

MAGNETIC RESONANCE IMAGING

The hippocampus is one of the first brain regions affected in patients with AD. Previous studies26 suggest that hippocampal atrophy, as measured using MRI, may be a marker for early AD in patients with MCI and may predict a more rapid deterioration to clinically defined AD. In this MCI trial, MRIs were obtained before baseline at a subset of sites with the ability to perform MRIs conforming to a specified protocol. Volume measurements of the hippocampi were performed by research associates who were masked to clinical information to ensure that the volumetric data were unbiased.27 The borders of the hippocampi were manually traced on the workstation screen for each image slice sequentially from posterior to anterior using previously described methods.28

We compared the baseline hippocampal volumes of patients with MCI participating in the Memory Impairment Study with hippocampal volumes of controls, patients with MCI, and patients with AD evaluated separately at the Mayo Clinic. To control for variation in head size, the hippocampal volumes for each individual were summed and divided by the total intracranial volume of that particular patient. Age- and sex-specific normal percentiles were determined for normalized hippocampal volume in a group of cognitively normal older controls. The control subjects used for this purpose were recruited from the community through primary care practices.28 Age- and sex-specific normal percentiles for the hippocampal volume measure for each patient with MCI were determined using this normal-value database. Each percentile was then converted to a W score. The W score is the value from a standard normal distribution corresponding to the observed percentile in control subjects. For example, for a standard normal distribution, the 50th, 5th, and 2.5th percentiles are give by W scores of 0, −1.64, and –1.96, respectively.

DATA ANALYSIS

Statistical analyses were conducted using a statistical software package (SPSS 11.0; SPSS Inc, Chicago, Ill). Demographic data that were continuous in nature were analyzed using analysis of variance, and categorical data were analyzed using χ2 statistics. Pairwise group comparisons were considered statistically significant if P<.05 after Bonferroni adjustment for multiple comparisons. Cognitive and functional measures were analyzed using general linear models in which the diagnostic group was entered as a fixed effect, with age, sex, education, ethnicity, and apolipoprotein E ϵ4 status included as covariates. Pairwise group comparisons in these analyses were considered significant if P<.05 after Bonferroni adjustment for multiple comparisons. To estimate the degree of impairment in patients with MCI, standardized z scores were calculated based on the mean and SD scores of the ADAS-Cog and other instruments from the neuropsychologic test battery administered to the control group. The z score indicates the relative degree of impairment from normal in SD units, thereby allowing comparison with other instruments.

A total of 769 patients were recruited in the MCI study, and baseline data were collected . One hundred seven cognitively normal elderly controls and 305 patients with mild AD were recruited for comparison purposes on the assessment measures. The demographic characteristics of the participants are given in Table 1. Patients with MCI were similar in age (mean age, 73 years) to patients with AD but were on average approximately 3 years older than controls. The educational level was similar among the MCI, control, and AD CDR 0.5 groups but slightly lower in the AD CDR 1.0 group. Patients with MCI reported an average duration of symptoms of approximately 3.1 years, which was about 0.6 years less than AD CDR 0.5 patients and approximately 1.2 years less than AD CDR 1.0 patients. Men were equally represented among the MCI and AD groups but were relatively less represented among controls. Patients with MCI were much more likely to carry the apolipoprotein E ϵ4 allele than controls but were less likely to carry it than patients with AD. Patients with MCI were 92% white, a frequency similar to that observed in the AD groups but greater than that observed in the control group, which had a greater representation of minorities.

Table Graphic Jump LocationTable 1 Demographic Characteristics of the Participant Groups

Mean scores on the screening measures (MMSE, paragraph recall, CDR, Hamilton scale, and Hachinski scale), the Global Deterioration Scale, and the MCI-ADL are given in Table 2. Patients with MCI had a mean MMSE score of 27.3 and a delayed paragraph recall score of 3.3. The MMSE score was intermediate between that of controls and patients with AD CDR 0.5 and significantly different from both groups. The immediate and delayed paragraph recall scores were significantly lower than those in controls (the paragraph recall test was not performed in patients with AD). The mean CDR sum of boxes score was 1.8 for patients with MCI, a value significantly lower than that observed in AD CDR 0.5 patients (3.0) and AD CDR 1.0 patients (6.2). Similarly, patients with MCI were significantly less impaired than patients with AD CDR 0.5 in all individual box scores on the CDR except personal care, which was not impaired in either group. As might be expected, the MCI group had its greatest impairment in the memory domain (mean = 0.6) compared with the other CDR domains. Scores on the CDR sum of boxes and the CDR domains are shown graphically in Figure 1. The MCI group had a significantly higher mean Hamilton score than controls. Patients with MCI had a significantly lower score on the MCI-ADL scale (designed to be sensitive to very mild impairments in instrumental ADLs) than controls (Table 2).

Table Graphic Jump LocationTable 2 Baseline Assessments: MMSE, Logical Memory, CDR, Hamilton, Hachinski, GDS, and ADCS MCI-ADL*
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Figure 1.

Mean Clinical Dementia Rating (CDR) domain scores in patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global CDR 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location

Patients with MCI had mean ADAS-Cog scores intermediate between those of controls and AD CDR 0.5 patients (Table 3 and Figure 2). Subscores on the ADAS-Cog are shown graphically in Figure 3 for controls, patients with MCI, and patients with AD. As can be seen in Table 3 and Figure 3, controls gained 0.9 error points on non–word list items on the ADAS-Cog compared with a gain of 2.1 points for patients with MCI, 5.7 points for patients with AD CDR 0.5, and 10.7 points for patients with AD CDR 1.0. In terms of z scores (SD units), patients with MCI performed on average 1.8 SD higher on the immediate word list recall test and 2.1 SD higher on the delayed word list recall test from the ADAS-Cog compared with 1.0 SD higher on the non–word list items (Table 3). Examination of the subitems from the ADAS-Cog revealed that, similar to controls, patients with MCI gained most of their error points (81%) on the word list recall and recognition items.

Table Graphic Jump LocationTable 3 ADAS-Cog Scores by Participant Groups*
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Figure 2.

Mean Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) total scores for controls, patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global Clinical Dementia Rating (CDR) 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location
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Figure 3.

Mean Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) subscores for controls, patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global Clinical Dementia Rating (CDR) 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location

The neuropsychologic battery was performed only in controls and patients with MCI (Table 4 and Figure 4). Compared with the control group, the results indicate that the largest decline from normal was observed on the New York University paragraph delayed recall (1.5 SD) and the New York University paragraph immediate recall test (1.2 SD) (Table 4). Beyond these memory tasks, the greatest impairment was seen on the Symbol Digit Modalities test and the category fluency tasks, although these deviated from normal by 1 SD or less.

Table Graphic Jump LocationTable 4 Neuropsychologic Measures in the Control and MCI Groups*
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Figure 4.

Performance on the Alzheimer's Disease Assessment Scale (ADAS)–Cognitive Subscale and the neuropsychologic test battery in patients with mild cognitive impairment (MCI) compared with controls. Mean z scores are shown with absolute values to illustrate relative worsening on each measure. NYU indicates New York University.

Graphic Jump Location

A subset of patients with MCI (n = 193) had MRIs performed and hippocampal volume measured at baseline. Patients with MCI in the Memory Impairment Study had hippocampal volumes that were virtually identical to those of patients with MCI from the Mayo Clinic described in a previous study by Jack et al,29 with mean ± SD hippocampal volumes (W = −1.2 ± 1.0) approximately 1.0 SD smaller than those of controls (W = −0.2 ± 1.2; P<.001) and 0.9 SD larger than those of patients with AD (W = −2.1 ± 1.2; P<.001).

The Memory Impairment Study represents one of the first attempts to perform a multicenter trial in individuals with MCI. Several studies on MCI have been conducted at single sites, but the ability to operationalize MCI criteria across sites has not been previously demonstrated, to our knowledge. Operationalizing these criteria, and determining whether they identify patients with characteristics different from those with mild AD, is an essential step if MCI is to become a valid treatment target.

In keeping with the recruitment criteria, the characteristics of this cohort indicated that they had primarily a prominent memory impairment but were also very mildly impaired in other cognitive domains. This is similar to the recruitment characteristics of other MCI studies in the literature.4,6,3032 There is some debate as to whether individuals with this degree of impairment might be considered to have dementia33; however, the experienced investigators in this study, after reviewing the available clinical and psychometric data, judged the participants in this MCI trial to be insufficiently impaired to warrant a clinical diagnosis of AD at the time they entered the study. Patients with MCI had higher ADAS-Cog total scores than controls, but the proportion of the points contributing to the ADAS-Cog total score derived from the word list memory tasks (81%) was similar to that of controls (84%). In contrast, only 68% and 58% of the points of the ADAS-Cog total were derived from the word list tasks for AD CDR 0.5 patients and AD CDR 1.0 patients, respectively. Patients with AD thus show a pattern of increasing involvement of nonmemory domains. Whereas patients with MCI performed about 1 SD below normal on the ADAS-Cog non–word list items, those with AD CDR 0.5 performed approximately 4 SD below normal (Table 3). Patients with MCI performed better than AD CDR 0.5 patients on all ADAS subscores except spoken language (Figure 3). Compared with AD CDR 0.5 patients, patients with MCI had generally preserved orientation. Patients with MCI gained only 0.5 error points on orientation compared with approximately 2 points gained for AD CDR 0.5 patients (Figure 3). Although orientation involves memory abilities, performance usually declines after more rigorous memory tests, for example, list learning procedures, have become impaired.

Performance by patients with MCI on the neuropsychologic battery further indicated that patients could be consistently recruited with the profile of a clearly defined memory impairment but only mild impairments in other cognitive domains. Patients with MCI performed, on average, less than 1 SD below normal on nonmemory cognitive measures included in the battery. As noted by other investigators,34 tests of learning, attention, perceptual speed, category fluency, and executive function may be impaired in patients with MCI, but these are far less prominent than the memory deficit.

In patients with clear memory impairment, one would expect to see a degree of functional impairment. This was relatively mild on the CDR and ADCS-ADL scales. The fact that patients with MCI were rated significantly better than those with AD CDR 0.5 on the CDR sum of boxes and CDR domains, including orientation, judgment, hobbies, and community affairs (Table 2), suggests that the extent of decline in these domains is inconsistent with the diagnosis of AD to a clinician.

The hippocampal volumes for a subset of patients with MCI in this study were similar to those reported by Jack et al,26,29 that is, approximately 1 SD below normal. As previously reported,26,35 patients with MCI and hippocampal atrophy have an increased likelihood of developing AD. The consistency of these data suggests that the patients with MCI recruited in this study are likely to have a pathological basis for their memory impairment and an increased likelihood of developing AD.36

The diagnosis of MCI was established with clinical efficiency using a simple memory test (paragraph recall) to establish an objective memory deficit, a measure of general cognition (MMSE) to exclude a broader cognitive decline beyond memory, and a structured clinical interview (CDR) with patients and caregivers to verify the patient's memory complaint and memory loss and to ensure that the patient was not demented. Diagnosis was made on clinical grounds and not algorithmically determined by neuropsychologic tests or other rating instruments. Results of recent studies37 have indicated that the concept of MCI can be unstable if only neuropsychologic criteria are arbitrarily retrofitted to data without clinical judgment being used.

In summary, our operational criteria for MCI were successful in identifying patients with MCI who had characteristics distinguishable from cognitively normal elderly controls and very mildly impaired AD patients. The clinical, neuropsychologic, functional, neuroimaging, and genetic profiles of patients with MCI are all consistent with a transitional stage between the cognitive changes of normal aging and very mild AD. Based on the data presented in this article, AD prevention trials with patients with MCI seem to be a promising tool for detecting, intervening, and delaying clinical AD while the disease is still in a transitional clinical stage.

Corresponding author and reprints: Michael Grundman, MD, MPH, Alzheimer's Disease Cooperative Study, University of California, San Diego, 8950 Villa La Jolla Dr, Suite C227, La Jolla, CA 92037 (e-mail: mgrundman@ucsd.edu).

Accepted for publication September 5, 2003.

We thank Denise Brauer Schiller, BA, for her assistance in preparing the manuscript.

Author contributions: Study concept and design (Drs Grundman, Petersen, Ferris, Thomas, Aisen, Bennett, Foster, Galasko, Doody, Sano, Mohs, and Thal); acquisition of data (Drs Grundman, Petersen, Ferris, Thomas, Aisen, Foster, Jack, Doody, Kaye, Sano, Mohs, Gauthier, Mulnard, van Dyck, and Zamrini, Mr Schultz, and Ms Schafer); analysis and interpretation of data (Drs Grundman, Petersen, Aisen, Foster, Jack, Galasko, Doody, Mohs, Jin, van Dyck, Mintzer, and Cahn-Weiner and Mr Kim); drafting of the manuscript (Drs Grundman, Petersen, Jin, and Mintzer, Messrs Kim and Schultz, and Ms Schafer); critical revision of the manuscript for important intellectual content (Drs Grundman, Petersen, Ferris, Thomas, Aisen, Bennett, Foster, Jack, Galasko, Doody, Kaye, Sano, Mohs, Gauthier, Mulnard, van Dyck, Mintzer, Zamrini, Cahn-Weiner, and Thal and Mr Schultz); statistical expertise (Drs Grundman, Jin, and van Dyck and Mr Kim); obtained funding (Drs Grundman, Thomas, Doody, Mohs, and Thal); administrative, technical, and material support (Drs Grundman, Ferris, Thomas, Aisen, Bennett, Foster, Jack, Sano, Mohs, and Zamrini, Mr Schultz, and Ms Schafer); study supervision (Drs Grundman, Petersen, Ferris, Foster, Jack, and Gauthier and Mr Schultz).

This study was supported by grant AG010483 from the National Institute on Aging. Additional financial support was provided by Pfizer Inc and Eisai Inc. Study medication was provided by Pfizer Inc, Eisai Inc, and Roche Vitamins Inc. Additional funding for the MRI component of the trial was provided from the Institute for the Study of Aging.

Study Participants

Affiliated Research Institute, San Diego, Calif: Charles H. Merideth, MD; Tara A. Milbrand, MSW; Sylvia Mende, PhD; Arizona Health Sciences Center, Tucson: Geoffrey Ahern, MD, PhD; Carol Kells, MS; Keith Burton; Barrow Neurology Clinic, Phoenix, Ariz: Arthur Schwartz, PhD; Charles Echols, MD; Marci Zomok, RN; Lauren Dawson, PhD; Baumel-Eisner Boca Raton, Boca Raton, Fla: Barry Baumel, MD; Janella Crasto; Rebecca Radzivill; Baumel-Eisner Ft Lauderdale, Ft Lauderdale, Fla: Larry Eisner, MD; Jorge Riveros; Amy Johnson, MA; Baumel-Eisner Miami Beach, Miami Beach, Fla: Barry Baumel, MD; Janella Crasto, MD; Damaris Alonso, MS; Alex Torres, LCSW, FAACS; Baylor College of Medicine, Houston, Tex: Rachelle Smith Doody, MD, PhD; Jamie Sims; Nikita Robinson; Brown University, Pawtucket, RI: Brian Ott, MD; Melissa Clemens, BS; Janet Grace, PhD; Burke Medical Research Institute, White Plains, NY: John Blass, MD, PhD; Rosanna Cirio, MA; ClinSearch, Inc, Kenilworth, NJ: Mark Roffman, PhD; Ina Marritt, BS; Cognitive Neurology, St Joseph's Health Center, London, Ontario: Andrew Kertesz, MD; Darlyne Morlog; Columbia University, New York, NY: Mary Sano, PhD; Evelyn Dominguez, MD; Alba Raganuth; Rafeal Santiago; Christine Weber; Dartmouth University, Neurology Studies Group, Lebanon, NH: David J. Coffey, MD; Pauline R. LeBlanc; Barbara A. Baker; Duke University Medical Center, Durham, NC: James Burke, MD, PhD; Sarah Vann Wyne; Michelle McCart, BA; E. Bruyere Memory Disorder Research, Ottawa, Ontario: Danilo A. Guzman, MD; Carole Gravelle; Isabelle Bedirian; Emory University, Atlanta, Ga: Allan Levey, MD, PhD; Janet Cellar, MSN; Nancy Gauchman, BS; Svati Valia; Fletcher Allen Health Care, Burlington, Vt: Paul A. Newhouse, MD; Elaine Gay; Geriatric Medical Research Group, Halifax, Nova Scotia: Sultan Darvesh, MD, PhD; Joanne Cross, RN, CCRC; Glenda Sherwood; Glenrose Rehabilitation Hospital, Edmonton, Alberta: Peter McCracken, MD; Sophie Aloisio, RN; Sandra Duban; Cathy McKelvey; Indiana University, Indianapolis: Martin Farlow, MD; Patricia Nurnberger, RN; Kathleen Fleming; Nenette Jessup, MS; Jean Pearson; Elizabeth Riley; Jewish Hospital Memory Clinic, Montreal, Quebec: Howard Chertkow, MD; Chris Hosein, MEd; The Johns Hopkins University, Baltimore, Md: Jason Brandt, PhD; Cynthia Munro, PhD; Sandy Kilada; Sean O'Donnell; Kansas University, Kansas City: Grisel J. Lopez, MD; Phyllis Switzer; Maimonides Medical Center, Brooklyn, NY: Aaron Miller, MD; Theresa La Rocca, RN, BSN; Steven Freimark; Massachusetts General, Boston, Boston: John Growdon, MD; Marsha Tennis, RN; Mayo Clinic, Jacksonville, Fla: Neill Graff-Radford, MD; Francine Parfitt, MSC, CCRC; Lauren M. Makarov, BS; Mayo Clinic, Rochester, Minn: David S. Knopman, MD; Bradley Boeve, MD; Nancy Haukom, RN, BAN; Martha Mandarino, BA; Diane Mullinax, BA; Ronald Petersen, MD, PhD; McGill Centre for Studies in Aging, Verdun, Quebec: Serge Gauthier, MD; Donna Amyot, RN, MScA, CCRC; MCP Hahnemann University, Philadelphia, Pa: Carol Lippa, MD; Anne M. Wilson, BS; Ralph Petrucci, EdD, ABPP; Medical University of South Carolina, North Charleston: Don Bagwell; Jacobo E. Mintzer, MD; Marilyn Stuckey, BSN, RNC; Memory Disorders Institute, Manchester, NJ: Joshua Shua-Haim, MD, FACP, AGSF; Vered Shua-Haim, RN; Mt Sinai School of Medicine, Bronx, NY: Kenneth Davis, MD; Richard C. Mohs, PhD; Kristin Swedish; Maria Casadiego; Lillian Negroni; Kelly Ware; Beverly Knox, RN; Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY: Nunzio Pomara, MD; Corazon de la Pena, MD; New York University Medical Center, New York: Steven Ferris, PhD; Maria Vlassopoulos; Janet Kastelan; Jessica Lam, BA; Northwestern University, Chicago, Ill: M. Marsel Mesulam, MD; Laura Herzog, MA; Oregon Health & Science University, Portland: Jeffrey Kaye, MD; Joyce Lear, RN, MN; Sarah Berman, BA; Kathy Wild, PhD; Palm Beach Neurological, West Palm Beach, Fla: Donna Cipriani, PhD, LMHC; Carl Sadowsky, MD; Yara Ramirez-Rojas, MD; Princeton Biomedical Research, Princeton, NJ: Abraham A. Sugerman, MD; Joan P. Cole-Kady, CRC; Ken Alvarez; Robbie Soika; Rush-Presbyterian–St Luke's Medical Center, Chicago: Neelum Aggarwal, MD; David Bennett, MD; Rose Marie Ferraro, LVN; Christopher Aldridge, BA; Michael Li, BA; Renarda M. Nance; Southern Illinois University, Springfield, Ill: Sandy Vicari, MA; Frances Schaefer, RN; Southwestern Vermont Medical Center, Bennington: Paul Solomon, PhD; Betty Jean Hathaway, LPN; Linda Crowe, MEd; Madeline Robinson, BA; Sunnybrook Health Sciences, Toronto, Ontario: Sandra Black, MD; Joanne Lawrence; Maureen Evans; State University of New York, Stony Brook, Stony Brook: Lauren Krupp, MD; Dawn M. Madigan, RN; Sutter Institute for Medical Research, Sacramento, Calif: William J. Au, MD; Deborah N. Poff, LVN; Monica Mulligan, RN, BSN; Iris Orengo, RN; University of British Columbia Clinic for Alzheimer's Disease, Vancouver: Howard Feldman, MD; Valarie O'Neill, RN; Karen Gilchrist, BA; University of Calgary Cognitive Assessment Clinic, Calgary, Alberta: David Hogan, MD; Pam Mueller; University Hospitals of Cleveland, Cleveland, Ohio: David Geldmacher, MD; Cony Santillan, MD; Parisa Talea, BS; Marianne Sanders, RN; University of California, Davis, Davis: Charles DeCarli, MD; Jean Coleman, RN, MSN; University of California, Irvine, Irvine: Carl Cotman, PhD; Ruth Mulnard, RN, DNSc; Catherine McAdams-Ortiz, RN, MSN, GNP; Hyunmie Kim, RN, MSN, GNP; University of California, Los Angeles, Los Angeles: Jeffrey Cummings, MD; Donna L. Masterman, MD; Michele F. Carter, RN; Nicole Bennett, MA; Laurie Berndt, BS; University of California, San Diego, La Jolla: John M. Olichney, MD; Susan M. Johnson, NP; Cecily W. Jenkins, MD; University of California, San Francisco, San Francisco: Kristine Yaffe, MD; Rosalie Gearhart, RN, MS; Virginia Smith, BS; University of Kentucky, Lexington: Frederick Schmitt, PhD; Jenny Cox, BSN; Sonya Anderson; Chantel Sowards Dearth, BA; University of Miami, Gulf Coast Education & Research, Port Charlotte, Fla: Jesus Rivero, MD; Raymond Ownby, MD, PhD; Jill Williams, LPN; University of Michigan, Ann Arbor: Norman Foster, MD; Joanne Lord; Nakia Johnson; University of Minnesota, Minneapolis: Angie Hochhalter; University of Nevada, School of Medicine, Las Vegas: Charles Bernick, MD; Gail Vranesh, RN, CCRC; Donna Munic, PhD; Pauline LeBlanc; University of New Mexico, Albuquerque: John Adair, MD; Sandra McClelland, RN; University of Pennsylvania, Philadelphia: Christopher Clark, MD; Kris Gravanda, BA; Valerie Cotter, MSN, CRNP; Jessica Nuñez; Elizabeth Ryan-Ripp; University of Pittsburgh, Pittsburgh, Pa: Steven DeKosky, MD; Lori Smith-Macedonia, PA-C, MPH; Thomas Baumgartner, MSW; April L. Kane, MSW; University of Rochester Medical Center, Rochester, NY: Pierre Tariot, MD; Bonnie Goldstein; Linda Terwilliger, BSN; University of South Florida, Tampa: Eric Pfeiffer, MD; Barbara Luhn, MSW; Dorothy Baxter, MPH; Jennifer Hunter, MA; University of Southern California, Los Angeles: Lon Schneider, MD; Nansi Taggart, RN, MA, BSN; Karen Stevens-Dagerman, MA; The University of Texas Southwestern Medical Center, Dallas: Myron Weiner, MD; Kristin Martin-Cook, MS; Taylor Ninman; Suzanne Pierce, BA; University of Washington, Seattle: Elaine Peskind, MD; Murray Raskind, MD; Rebecca Wood, BS; Nancy Brown, CCRC; James O'Connell, MHP; Nghia Pham; VA Medical Center, Augusta, Augusta, Ga: Martha E. Nichols, MD; Carolyn Bailey, MS; Dennis Hillesland, MS; Vanderbilt University, Nashville, Tenn: Richard Margolin, MD; Diane Kent, RN; Lynne McFarland, MSN, EEd; Wien Center, Miami Beach, Fla: Ranjan Duara, MD; Peggy D. Roberts; Yale University School of Medicine, New Haven, Conn: Christopher Van Dyck, MD; Martha MacAvoy, PhD; Lisa Cretella; Tracy Rightmer; Lorien Zeiser, RN, MA.

Mild Cognitive Impairment to Alzheimer Disease Conversion Adjudication Committee

David A. Bennett, MD, Rush Alzheimer's Disease Center, Rush Presbyterian–St Luke's Medical Center; Rachelle Doody, MD, PhD, Baylor College of Medicine Alzheimer's Disease Research Center; Steven H. Ferris, PhD, Department of Psychiatry, New York University School of Medicine; Douglas R. Galasko, MD, University of California, San Diego; Jeffrey Kaye, MD, Oregon Health & Science University and the Portland Veterans Affairs Medical Center.

Data and Safety Monitoring Board

Karl Kieburtz, MD, University of Rochester; Trey Sunderland, MD, National Institute of Mental Health, National Institutes of Health Clinical Center, Bethesda, Md; Charles C. Berry, PhD, University of California, San Diego.

Petersen  RC Conceptual issues.  In: Petersen  RC, ed. Mild Cognitive Impairment: Aging to Alzheimer's Disease. New York, NY: Oxford University Press; 2003:114.
Petersen  RCDoody  RKurz  A  et al Current concepts in mild cognitive impairment. Arch Neurol.2001;58:1985-1992.
PubMed
Bowen  JTeri  LKukull  WMcCormick  WMcCurry  SMLarson  EB Progression to dementia in patients with isolated memory loss. Lancet.1997;349:763-765.
PubMed
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol.1999;56:303-308.
PubMed
Devanand  DPFolz  MGorlyn  MMoeller  JRStern  Y Questionable dementia: clinical course and predictors of outcome. J Am Geriatr Soc.1997;45:321-328.
PubMed
Petersen  RCStevens  JCGanguli  MTangalos  EGCummings  JLDeKosky  ST 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.
PubMed
Grundman  MPetersen  RCMorris  JC  et al Rate of dementia of Alzheimer type (DAT) in subjects with mild cognitive impairment: the Alzheimer's Disease Cooperative Study [abstract]. Neurology.1996;46:A403.
Petersen  RCMorris  JC Clinical features.  In: Petersen  RC, ed. Mild Cognitive Impairment: Aging to Alzheimer's Disease. New York, NY: Oxford University Press; 2003:1539.
Grundman  M Vitamin E and Alzheimer disease: the basis for additional clinical trials. Am J Clin Nutr.2000;71:630S-636S.
PubMed
Grundman  MDelaney  P Antioxidant Strategies for Alzheimer's Disease. Proc Nutr Soc.2002;61:191-202.
PubMed
Petersen  RC Mild cognitive impairment clinical trials. Nat Rev Drug Discov.2003;2:646-653.
PubMed
Mohs  RCKnopman  DPetersen  RC  et al Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale (ADAS) that broaden its scope: the Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord.1997;11(suppl 2):13S-21S.
Wechsler  D WMS-R Wechsler Memory Scale—Revised Manual.  New York, NY: Psychological Corporation, Harcourt Brace Jovanovich Inc; 1987.
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res.1975;12:189-198.
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology.1984;34:939-944.
PubMed
Rosen  WGTerry  RDFuld  PAKatzman  RPeck  A Pathological verification of ischemic score in differentiation of dementias. Ann Neurol.1980;7:486-488.
PubMed
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry.1960;23:56-62.
PubMed
Galasko  DRBennett  DSano  M  et al An inventory to assess activities of daily living for clinical trials in Alzheimer's disease: the Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord.1997;11(suppl 2):S33-S39.
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry.1982;139:1136-1139.
PubMed
Kluger  AFerris  SHGolomb  JMittelman  MSReisberg  B Neuropsychological prediction of decline to dementia in nondemented elderly. J Geriatr Psychiatry Neurol.1999;12:168-179.
PubMed
Smith  A Symbol Digit Modalities Test Manual–Revised.  Los Angeles, Calif: Western Psychological Services; 1982.
Monsch  AUBondi  MWButters  NSalmon  DPKatzman  RThal  LJ Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type. Arch Neurol.1992;49:1253-1258.
PubMed
Kaplan  EFGoodglass  HWeintraub  S Boston Naming Test.  Philadelphia, Pa: Lea & Febiger; 1983.
Wechsler  D Manual for the Wechsler Adult Intelligence Scale.  Rev ed. New York, NY: Psychological Corporation, Harcourt Brace Jovanovich Inc; 1981.
Aisen  PSSchafer  KAGrundman  M  et al Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA.2003;289:2819-2826.
PubMed
Jack Jr  CRPetersen  RCXu  YC  et al Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology.1999;52:1397-1403.
PubMed
Jack Jr  CRBentley  MTwomey  CKZinsmeister  AR MR-based volume measurements of the hippocampal formation and anterior temporal lobe: validation studies. Radiology.1990;176:205-209.
PubMed
Jack Jr  CRPetersen  RCXu  YC  et al Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology.1997;49:786-794.
PubMed
Jack  CRPetersen  RCXu  Y  et al Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology.2000;55:484-489.
PubMed
Celsis  P Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer's disease? Ann Med.2000;32:6-14.
PubMed
Daly  EZaitchik  DCopeland  MSchmahmann  JGunther  JAlbert  M Predicting conversion to Alzheimer disease using standardized clinical information. Arch Neurol.2000;57:675-680.
PubMed
Fox  NCCrum  WRScahill  RIStevens  JMJanssen  JCRossor  MN Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images. Lancet.2001;358:201-205.
PubMed
Morris  JCStorandt  MMiller  JP  et al Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol.2001;58:397-405.
PubMed
Bozoki  AGiordani  BHeidebrink  JLBerent  SFoster  NL Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol.2001;58:411-416.
PubMed
Killiany  RJGomez-Isla  TMoss  M  et al Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol.2000;47:430-439.
PubMed
Grundman  MDrahomira  SJack Jr  CR  et al Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial. J Mol Neurosci.2002;19:23-27.
PubMed
Ritchie  KArtero  STouchon  J Classification criteria for mild cognitive impairment: a population-based validation study. Neurology.2001;56:37-42.
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Mean Clinical Dementia Rating (CDR) domain scores in patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global CDR 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Mean Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) total scores for controls, patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global Clinical Dementia Rating (CDR) 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Mean Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) subscores for controls, patients with mild cognitive impairment (MCI), patients with Alzheimer disease (AD) and global Clinical Dementia Rating (CDR) 0.5, and patients with AD and global CDR 1.0.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Performance on the Alzheimer's Disease Assessment Scale (ADAS)–Cognitive Subscale and the neuropsychologic test battery in patients with mild cognitive impairment (MCI) compared with controls. Mean z scores are shown with absolute values to illustrate relative worsening on each measure. NYU indicates New York University.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1 Demographic Characteristics of the Participant Groups
Table Graphic Jump LocationTable 2 Baseline Assessments: MMSE, Logical Memory, CDR, Hamilton, Hachinski, GDS, and ADCS MCI-ADL*
Table Graphic Jump LocationTable 3 ADAS-Cog Scores by Participant Groups*
Table Graphic Jump LocationTable 4 Neuropsychologic Measures in the Control and MCI Groups*

References

Petersen  RC Conceptual issues.  In: Petersen  RC, ed. Mild Cognitive Impairment: Aging to Alzheimer's Disease. New York, NY: Oxford University Press; 2003:114.
Petersen  RCDoody  RKurz  A  et al Current concepts in mild cognitive impairment. Arch Neurol.2001;58:1985-1992.
PubMed
Bowen  JTeri  LKukull  WMcCormick  WMcCurry  SMLarson  EB Progression to dementia in patients with isolated memory loss. Lancet.1997;349:763-765.
PubMed
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol.1999;56:303-308.
PubMed
Devanand  DPFolz  MGorlyn  MMoeller  JRStern  Y Questionable dementia: clinical course and predictors of outcome. J Am Geriatr Soc.1997;45:321-328.
PubMed
Petersen  RCStevens  JCGanguli  MTangalos  EGCummings  JLDeKosky  ST 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.
PubMed
Grundman  MPetersen  RCMorris  JC  et al Rate of dementia of Alzheimer type (DAT) in subjects with mild cognitive impairment: the Alzheimer's Disease Cooperative Study [abstract]. Neurology.1996;46:A403.
Petersen  RCMorris  JC Clinical features.  In: Petersen  RC, ed. Mild Cognitive Impairment: Aging to Alzheimer's Disease. New York, NY: Oxford University Press; 2003:1539.
Grundman  M Vitamin E and Alzheimer disease: the basis for additional clinical trials. Am J Clin Nutr.2000;71:630S-636S.
PubMed
Grundman  MDelaney  P Antioxidant Strategies for Alzheimer's Disease. Proc Nutr Soc.2002;61:191-202.
PubMed
Petersen  RC Mild cognitive impairment clinical trials. Nat Rev Drug Discov.2003;2:646-653.
PubMed
Mohs  RCKnopman  DPetersen  RC  et al Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer's Disease Assessment Scale (ADAS) that broaden its scope: the Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord.1997;11(suppl 2):13S-21S.
Wechsler  D WMS-R Wechsler Memory Scale—Revised Manual.  New York, NY: Psychological Corporation, Harcourt Brace Jovanovich Inc; 1987.
Folstein  MFFolstein  SEMcHugh  PR "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res.1975;12:189-198.
PubMed
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology.1984;34:939-944.
PubMed
Rosen  WGTerry  RDFuld  PAKatzman  RPeck  A Pathological verification of ischemic score in differentiation of dementias. Ann Neurol.1980;7:486-488.
PubMed
Hamilton  M A rating scale for depression. J Neurol Neurosurg Psychiatry.1960;23:56-62.
PubMed
Galasko  DRBennett  DSano  M  et al An inventory to assess activities of daily living for clinical trials in Alzheimer's disease: the Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord.1997;11(suppl 2):S33-S39.
PubMed
Reisberg  BFerris  SHde Leon  MJCrook  T The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry.1982;139:1136-1139.
PubMed
Kluger  AFerris  SHGolomb  JMittelman  MSReisberg  B Neuropsychological prediction of decline to dementia in nondemented elderly. J Geriatr Psychiatry Neurol.1999;12:168-179.
PubMed
Smith  A Symbol Digit Modalities Test Manual–Revised.  Los Angeles, Calif: Western Psychological Services; 1982.
Monsch  AUBondi  MWButters  NSalmon  DPKatzman  RThal  LJ Comparisons of verbal fluency tasks in the detection of dementia of the Alzheimer type. Arch Neurol.1992;49:1253-1258.
PubMed
Kaplan  EFGoodglass  HWeintraub  S Boston Naming Test.  Philadelphia, Pa: Lea & Febiger; 1983.
Wechsler  D Manual for the Wechsler Adult Intelligence Scale.  Rev ed. New York, NY: Psychological Corporation, Harcourt Brace Jovanovich Inc; 1981.
Aisen  PSSchafer  KAGrundman  M  et al Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA.2003;289:2819-2826.
PubMed
Jack Jr  CRPetersen  RCXu  YC  et al Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology.1999;52:1397-1403.
PubMed
Jack Jr  CRBentley  MTwomey  CKZinsmeister  AR MR-based volume measurements of the hippocampal formation and anterior temporal lobe: validation studies. Radiology.1990;176:205-209.
PubMed
Jack Jr  CRPetersen  RCXu  YC  et al Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology.1997;49:786-794.
PubMed
Jack  CRPetersen  RCXu  Y  et al Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology.2000;55:484-489.
PubMed
Celsis  P Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer's disease? Ann Med.2000;32:6-14.
PubMed
Daly  EZaitchik  DCopeland  MSchmahmann  JGunther  JAlbert  M Predicting conversion to Alzheimer disease using standardized clinical information. Arch Neurol.2000;57:675-680.
PubMed
Fox  NCCrum  WRScahill  RIStevens  JMJanssen  JCRossor  MN Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images. Lancet.2001;358:201-205.
PubMed
Morris  JCStorandt  MMiller  JP  et al Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol.2001;58:397-405.
PubMed
Bozoki  AGiordani  BHeidebrink  JLBerent  SFoster  NL Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol.2001;58:411-416.
PubMed
Killiany  RJGomez-Isla  TMoss  M  et al Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease. Ann Neurol.2000;47:430-439.
PubMed
Grundman  MDrahomira  SJack Jr  CR  et al Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial. J Mol Neurosci.2002;19:23-27.
PubMed
Ritchie  KArtero  STouchon  J Classification criteria for mild cognitive impairment: a population-based validation study. Neurology.2001;56:37-42.
PubMed

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