 |
|
Mild Cognitive Impairment
Clinical Characterization and Outcome
Ronald C. Petersen, PhD, MD;
Glenn E. Smith, PhD;
Stephen C. Waring, DVM, PhD;
Robert J. Ivnik, PhD;
Eric G. Tangalos, MD;
Emre Kokmen, MD
Arch Neurol. 1999;56:303-308.
ABSTRACT
| |
Background Subjects with a mild cognitive impairment (MCI) have a memory impairment beyond that expected for age and education yet are not demented. These subjects are becoming the focus of many prediction studies and early intervention trials.
Objective To characterize clinically subjects with MCI cross-sectionally and longitudinally.
Design A prospective, longitudinal inception cohort.
Setting General community clinic.
Participants A sample of 76 consecutively evaluated subjects with MCI were compared with 234 healthy control subjects and 106 patients with mild Alzheimer disease (AD), all from a community setting as part of the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry, Rochester, Minn.
Main Outcome Measures The 3 groups of individuals were compared on demographic factors and measures of cognitive function including the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Dementia Rating Scale, Free and Cued Selective Reminding Test, and Auditory Verbal Learning Test. Clinical classifications of dementia and AD were determined according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, respectively.
Results The primary distinction between control subjects and subjects with MCI was in the area of memory, while other cognitive functions were comparable. However, when the subjects with MCI were compared with the patients with very mild AD, memory performance was similar, but patients with AD were more impaired in other cognitive domains as well. Longitudinal performance demonstrated that the subjects with MCI declined at a rate greater than that of the controls but less rapidly than the patients with mild AD.
Conclusions Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD. They appear to constitute a clinical entity that can be characterized for treatment interventions.
INTRODUCTION
A GREAT deal of interest has been generated concerning the topic of a boundary or transitional state between normal aging and dementia, or more specifically, Alzheimer disease (AD).1 This condition has received several descriptors including mild cognitive impairment (MCI), incipient dementia, and isolated memory impairment.2-4 Reviews of several studies have indicated that these individuals are at an increased risk for developing AD ranging from 1% to 25% per year.5 The variability in these rates likely reflects differing diagnostic criteria, measurement instruments, and small sample sizes.5
Patients with an MCI are also becoming of interest for treatment trials. The Alzheimer's Disease Cooperative Study, which is a National Institute on Aging consortium of Alzheimer's Disease research groups, is embarking on a multicenter trial of agents intended to alter the progression of patients with MCI to AD.6 Several pharmaceutical companies are initiating large trials on this same group of individuals.
Questions can be raised as to the diagnostic criteria for MCI. Some investigators believe that virtually all these patients with mild disease have AD neuropathologically, and, therefore, this may not be a useful distinction.7 Others6, 8-9 note that while many of these patients progress to AD, not all do, and consequently, the distinction is important.
We have been enrolling patients at the mild end of the cognitive spectrum for more than 10 years as part of a community study on aging and dementia.8, 10 Our recruitment scheme involves screening patients who are being seen by their primary care physicians for periodic general medical evaluations which affords us the opportunity to detect patients before they present to a dementia or memory disorders clinic. This study reports the clinical criteria used to diagnose these patients as well as their neuropsychological characterization, differentiation from controls and patients with mild AD, and the longitudinal course of the subjects with MCI. As such, these data provide a background for the clinician to use in evaluating these individuals in practice.
SUBJECTS AND METHODS
The subjects for this study were recruited through the Mayo Alzheimer's Disease Center/Alzheimer's Disease Patient Registry (ADC/ADPR) using a standardized clinical protocol.8-12 The patients were derived from 2 sources: community patients in Rochester, Minn, and regional patients referred to the ADC. The community patients were recruited through the Division of Community Internal Medicine of the Mayo Clinic from Rochester residents who were receiving their general medical care at the Mayo Clinic. If during the course of their medical evaluation the patients expressed concern about their cognitive function, the patients' families expressed a concern about the patients' cognition, or the examining physician detected a cognitive change in the patients, the patient was then referred to the ADC/ADPR staff. The regional patients were derived from individuals who had come to the Mayo ADC for an evaluation of cognitive difficulties. These individuals were either referred by their personal physicians, family members, or by the patients themselves.
Patients from both the community and regional sources received an identical evaluation. On referral, the patients were seen by a behavioral neurologist who obtained a medical history from the patient and corroborating sources, performed the Short Test of Mental Status,13-14 Hachinski Ischemic Scale,15 and a neurologic examination. Study personnel obtained other data including the Record of Independent Living,16 Geriatric Depression Scale,17 and additional family history information. Laboratory studies were performed, including a chemistry group, complete blood cell count, sedimentation rate, vitamin B12 and folic acid levels, sensitive thyroid-stimulating hormone level, and syphilis serologic testing. All patients received a head imaging study (computed tomography or magnetic resonance imaging). Additional studies including a cerebrospinal fluid analysis, electroencephalogram, and a single-photon emission computed tomographic scan were performed as the clinical situation indicated.
Two sessions of neuropsychological testing were completed on all subjects. The first set of tests was used for diagnostic purposes and included the Wechsler Adult Intelligence Scale–Revised, Wechsler Memory Scale–Revised, Auditory Verbal Learning Test, and Wide-Range Achievement Test-III.18 The second set of tests was used for research purposes and included the Mini-Mental State Examination (MMSE),19 Dementia Rating Scale (DRS),20 Free and Cued Selective Reminding Test,21-23 Boston Naming Test,24 Controlled Oral Word Association Test,25 and category fluency procedures.26
At the completion of this evaluation a consensus committee meeting was held involving the behavioral neurologists, geriatrician, neuropsychologists, nurses, and other study personnel who had evaluated the patients. Diagnoses were made for dementia and AD according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition,27 and the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders of Association criteria, respectively.28 The diagnosis of MCI was made if the patient met the following criteria: (1) memory complaint, (2) normal activities of daily living, (3) normal general cognitive function, (4) abnormal memory for age, and (5) not demented.8 Several studies3, 8-9 characterizing the outcome of patients with an MCI using these criteria have been reported. At the conclusion of the consensus conference, after the diagnosis had been made, the patients were staged on the Clinical Dementia Rating scale (CDR)29-30 and the Global Deterioration Scale.31
Control subjects were sought from the community population of individuals receiving general medical examinations at the Mayo Clinic.32-34 They underwent a similar evaluation as the patients described earlier including the neurologic examination and neuropsychological testing battery. They qualified as controls if, in the opinion of their clinician, they were functioning normally in the community and did not have a cognitive impairment. In addition, they could not have any active neurologic or psychiatric illnesses and could not be taking psychoactive medications. They could have comorbid illnesses such as hypertension and coronary artery disease, and they could be taking medications for these disorders. However, in the opinion of their physicians, these illnesses or their treatments did not interfere with the patients' cognitive function. These patients were also reviewed at the consensus conference and CDR scale and Global Deterioration Scale ratings were completed.
Patients and control subjects were reevaluated every 12 to 18 months and received an abbreviated neuropsychological battery at that visit. Their performance was reviewed at the consensus conference and the diagnoses were adjusted accordingly, if necessary. They were also reassessed on the CDR scale and the Global Deterioration Scale. The Mayo ADC/ADPR projects have been approved by the Mayo Institutional Review Board.
RESULTS
We have enrolled 76 subjects with the diagnosis of MCI over the last 11 years. The demographic features of these subjects as well as groups of control subjects and patients with very mild AD enrolled over the same interval grouped by CDR ratings are shown in Table 1 for comparison purposes. Table 1 also shows the performance of the 4 groups with respect to a sampling of cognitive measures. As would be consistent with the selection criteria, the subjects with MCI performed slightly more poorly on these measures than the control subjects, but were superior to the patients with AD. Statistical comparisons in Table 1 were performed using a 1-way analysis of variance with each cognitive measure as the dependent variable comparing the 4 groups of subjects. The relevant pairwise comparisons were made between adjacent groups, eg, control vs MCI and MCI vs AD (CDR 0.5) and AD (CDR 0.5) vs AD (CDR 1), using Tukey honestly significant difference with a level of significance being set at the .01 level due to the large number of comparisons performed.
|
|
|
|
Comparison of 4 Clinical Groups on Various Cognitive Scales*
|
|
|
As one measure of disease severity, the CDR sum of box scores was calculated.29-30 The CDR sum of the box scores was determined by totaling the individual box scores for a given patient (range, 0-18). For example, a control patient may have had 0 in each of the 6 boxes for the various categories. A typical patient with AD and a summary CDR score of 1 might have had the sum of the 6 having scored 1 in each of the 6 individual boxes. This statistic yielded an approximate index of severity on the CDR as well as involvement of activities of daily living.
On measures of general cognition such as the Wechsler Adult Intelligence Scale–Revised, the controls and subjects with MCI did not differ significantly. On the screening measures of general cognition, MMSE and DRS, there were small differences largely due to the memory component of those measures. In general, while the subjects with MCI did not perform as well as the control subjects, they still functioned in the normal range. However, the subjects with MCI differed from even the CDR 0.5 patients with AD on virtually all measures of general cognitive function (Figure 1).
|
|
|
|
Figure 1. Relative performance among 4 groups: controls, subjects with mild cognitive impairment (MCI) (Clinical Dementia Rating [CDR] 0.5), and patients with Alzheimer disease (AD) (CDR 0.5; CDR 1), on measures of global cognitive functioning, Mini-Mental State Examination (MMSE), and full-scale IQ compared with performance on measures of delayed recall for verbal materials (Logical Memory II) and nonverbal materials (Visual Reproductions II).
|
|
|
Table 1 displays memory data among the 4 groups. Again, as would be expected from the selection criteria, the subjects with MCI were significantly impaired on all memory measures relative to control subjects and appeared similar to the patients with AD. These results were seen for virtually all measures of learning and delayed recall using word lists, paragraphs, and nonverbal materials. The differences were less dramatic between the subjects with MCI and the patients with AD; rather, the other areas of cognition and functional measures differentiated these groups.
The Boston Naming Test results paralleled those of the memory domain. These findings can be interpreted as indicating that either the linguistic function of naming is impaired early in the disease process, or that this naming test actually assesses semantic memory and therefore is consistent with the other memory data.
Figure 2 demonstrates the outcome of the subjects with MCI up to approximately 4 years of follow-up. The conversion rate was 12% per year for the 4 years. These rates are in contrast to conversion rates for the healthy control subjects in our community sample. We have enrolled and followed up more than 500 control subjects in the 10 years of the study, and these subjects tend to convert to MCI/AD at a rate of approximately 1% to 2% per year.
|
|
|
|
Figure 2. Annual rates of conversion from mild cognitive impairment (MCI) to dementia over 48 months.
|
|
|
Figure 3 shows the mean annualized rate of change for all subjects in the comparison groups on the MMSE, DRS, and Global Deterioration Scale. On the MMSE, the subjects with MCI behaved more like control subjects than the patients with AD. Similarly, the subjects with MCI showed a slower rate of change on the DRS and Global Deterioration Scale with respect to annualized differences than did the patients with AD.
|
|
|
|
Figure 3. Annual rates of change on 3 measures of global function for controls, subjects with mild cognitive impairment (MCI) (Clinical Dementia Rating [CDR] 0.5), and patients with Alzheimer disease (AD) (CDR 0.5; CDR 1). MMSE indicates Mini-Mental State Examination.
|
|
|
COMMENT
This study was designed to quantitatively characterize and describe the clinical course of patients diagnosed as having MCI using criteria that are similar to those being adopted by several multicenter treatment trials. While the criteria for MCI can be accepted by investigators in principle, the operationalization of these criteria can be challenging. As such, these results provide cross-sectional and longitudinal data with respect to these criteria.
As expected, the subjects with MCI performed more similarly to the control subjects than the patients with AD on measures of general cognition and other nonmemory indexes. While there may have been mild impairments in some of the domains of cognition, eg, full-scale IQ, the actual raw score difference was sufficiently small, eg, a full-scale IQ of 101.8 vs 98.0 for controls and subjects with MCI, respectively, to not be clinically meaningful. That is, it is doubtful that most clinicians would say that a subject with a full-scale IQ of 98 was demented on the basis of this measure. The subjects with MCI performed more poorly than the control subjects on the Controlled Oral Word Association Test, but once again, the performance of the subjects with MCI was in the normal range for age based on our community studies.35 This is not to say, however, that these subjects may not have incipient clinical AD; rather, most clinicians would be reluctant to make the diagnosis of AD at this stage. In addition, it is not likely that these subjects have a significant functional deficit since their mean CDR sum of box scores was 1.5 with most of the decline being accounted for by memory deficits. However, the patients with very mild AD (CDR 0.5) had a mean CDR sum of the box score of 3.3 that reflected these subjects' impairment in functional domains.
From a memory perspective, the subjects with MCI appeared more like the patients with AD than the control subjects. Again, this is not surprising considering the selection criteria, but these data lend quantitation to these criteria. In fact, if the clinician sees a patient with impaired delayed recall performance or difficulty benefiting from semantic cues during learning or recall in the setting of relatively preserved general cognition, the diagnosis of MCI should be entertained.
Most of the subjects received the diagnosis of MCI at entry into the study, while a few of the subjects had converted from a prior normal control status. The documentation of a memory decline was largely historical and based on the interview with the subject. With respect to the quality of the memory complaints, we asked for changes in memory function with respect to items involving recent memory. We prefer corroboration by an informant who knows the patient well. Previous work36 has indicated that while individuals' subjective impressions of their memory function correlate best with indexes of depression, informants' assessments correlate well with objective performance.
Since the memory decline was subjective, it was necessary to corroborate memory performance as being abnormal (generally 1.5 SD below age- and education-matched control subjects) while general cognitive (Verbal IQ, Performance IQ) was within 0.5 SD of appropriate controls. The value of availability of an objectively documented decline in performance is helpful in detecting those subjects who are predisposed to develop AD.37
The clinical course of these subjects is important to describe. Individuals with MCI appear to be at an increased risk of developing AD at the rate of 10% to 12% per year. As Dawe et al5 have indicated, there is variability in the literature largely due to different clinical criteria, neuropsychological measures used, and small numbers of subjects. However, several recent studies1, 8, 38-39 using somewhat similar criteria, neuropsychological measures, and larger subject pools have demonstrated rates that are consistent with those reported herein.
Our previous work demonstrated that apolipoprotein E  4 carrier status and features of memory function may predict who is likely to progress to AD more rapidly.3, 8, 12, 38, 40 Magnetic resonance imaging volumetric measurements of the hippocampal formation may also be useful.41
There are 2 issues with respect to the classification of MCI and CDR 0.5 that need to be clarified. The first issue pertains to potential contamination of the MCI diagnosis with healthy individuals. As described earlier, it is possible that some subjects with MCI may have had long-standing poor memory function that may not progress. While the proportion of the total group of subjects with MCI who constitute long-standing poor performers is small, without longitudinal objective data, some of these individuals could be classified as MCI.
The other issue concerns the heterogeneity of the classification of a CDR score of 0.5. As Figure 1 demonstrates, some subjects with the classification of a CDR score 0.5 can be diagnosed as having MCI, while others may be designated as having AD. Essentially, those with a CDR score of 0.5 who have MCI have a significant memory impairment, but their other cognitive functions and activities of daily living are only slightly abnormal. Generally speaking, these deficits are of insufficient magnitude to constitute the diagnosis of AD by most clinicians. Those with a CDR score of 0.5 who qualify for the diagnosis of AD are more likely to be impaired in other areas of cognition ( 1.0 SD below healthy subjects on Verbal IQ, Performance IQ, MMSE, and DRS) and are functionally impaired (CDR sum of boxes, Global Deterioration Scale). These individuals meet the criteria for very mild AD and are distinguishable from the subjects with MCI.
All the classifications discussed are clinical. While the diagnoses are supported by neuropsychological data, the ultimate judgment is that of a clinician. Most clinicians would be uncomfortable at classifying subjects with MCI as having AD based on the criteria described.
The rates of change of subjects with MCI are different from control subjects and patients with AD. It is noteworthy that the control subjects improved from baseline to first follow-up on the full-scale IQ, which is a documented phenomenon.42 This makes the decline of the MCI group meaningful, albeit small. These subjects change on the global instruments more rapidly than control subjects but not as rapidly as the clinically diagnosed patients with AD. This could reflect several factors. It is possible that the measuring instruments are not linear and are less sensitive to changes in the more mild states. It is also possible that the MCI group is "contaminated" with essentially healthy subjects who are not going to progress to AD. This difference can also be used to argue that not all subjects with MCI have AD at this point in time.
As is apparent, there are many interesting questions surrounding subjects with MCI. This study was designed to lend quantitative characterization to the clinical criteria for MCI that are being used in several multicenter trials. It also documents the clinical course of these subjects over the years with respect to their changes on standard instruments and their diagnostic outcomes. These results demonstrated that these subjects are at increased risk of progressing to AD and are useful to characterize for both theoretical and practical purposes.
AUTHOR INFORMATION
Accepted for publication October 7, 1998.
This study was supported by grants AG06786 and AG08031 from the National Institute on Aging, Bethesda, Md.
We thank Ruth Cha, MS, for statistical assistance and Jackie Evans for secretarial expertise. We also thank the staff of the Mayo Alzheimer's Disease Center and the Mayo Alzheimer's Disease Patient Registry, Rochester, Minn, for evaluation and care of patients.
Reprints: Ronald C. Petersen, PhD, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
From the Departments of Neurology (Drs Petersen and Kokmen), Health Sciences Research (Drs Petersen and Waring), and Psychiatry and Psychology (Drs Smith and Ivnik), and the Division of Community Internal Medicine (Dr Tangalos), Mayo Clinic, Rochester, Minn.
REFERENCES
| |
1. Petersen RC. Normal aging, mild cognitive impairment, and early Alzheimer's disease. Neurologist. 1995;1:326-344.
ISI
2. Flicker C, Ferris SH, Reisberg B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology. 1991;41:1006-1009.
FREE FULL TEXT
3. Tierney MC, Szalai JP, Snow WG, et al. A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology. 1996;46:149-154.
FREE FULL TEXT
4. Minoshima S, Giordani B, Berent S, Frey K, Foster N, Kuhl D. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997;42:85-94.
FULL TEXT
|
ISI
| PUBMED
5. Dawe B, Procter A, Philpot M. Concepts of mild memory impairment in the elderly and their relationship to dementia: a review. Int J Geriatr Psychiatry. 1992;7:473-479.
6. Grundman M, Petersen R, Morris J, et al. Rate of dementia of the Alzheimer type (DAT) in subjects with mild cognitive impairment [abstract]. Neurology. 1996;46:A403.
7. Morris JC, McKeel DW, Storandt M, et al. Very mild Alzheimer's disease: informant based clinical, psychometric, and pathologic distinction from normal aging. Neurology. 1991;41:469-478.
FREE FULL TEXT
8. 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;273:1274-1278.
FREE FULL TEXT
9. Petersen RC, Waring SC, Smith GE, Tangalos EG, Thibodeau SN. Predictive value of APOE genotyping in incipient Alzheimer's disease. Ann N Y Acad Sci. 1996;802:58-69.
ISI
| PUBMED
10. Petersen RC, Kokmen E, Tangalos E, Ivnik RJ, Kurland LT. Mayo Clinic Alzheimer's Disease Patient Registry. Aging. 1990;2:408-415.
PUBMED
11. Petersen RC, Smith G, Kokmen E, Ivnik RJ, Tangalos EG. Memory function in normal aging. Neurology. 1992;42:396-401.
FREE FULL TEXT
12. Petersen RC, Smith GE, Ivnik RJ, Kokmen E, Tangalos EG. Memory function in very early Alzheimer's disease. Neurology. 1994;44:867-872.
FREE FULL TEXT
13. Kokmen E, Naessens JM, Offord KP. A Short Test of Mental Status: description and preliminary results. Mayo Clin Proc. 1987;62:281-288.
ISI
| PUBMED
14. Kokmen E, Smith GE, Petersen RC, Tangalos E, Ivnik RJ. The short test of mental status: correlations with standardized psychometric testing. Arch Neurol. 1991;48:725-728.
FREE FULL TEXT
15. Rosen W, Terry R. Pathological verification of ischemic score differentiation of dementias. Ann Neurol. 1980;7:486-488.
FULL TEXT
|
ISI
| PUBMED
16. Weintraub S. The record of independent living: an informant-completed measure of activities of daily living and behavior in elderly patients with cognitive impairment. Am J Alzheimer Care Rel Disord. 1986;7:35-39.
17. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Brink TL, ed. Clinical Gerontology: A Guide to Assessment and Intervention. Binghamton, NY: Haworth Press Inc; 1986:165-173.
18. Lezak MD. Neuropsychological Assessment, Third Edition. New York, NY: Oxford University Press Inc; 1995.
19. Folstein MF, Folstein SE, McHugh PR. "Mini-Mental State": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
FULL TEXT
|
ISI
| PUBMED
20. Mattis S. Dementia Rating Scale: Professional Manual. Odessa, Fla: Psychological Assessment Resources Inc; 1988.
21. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol. 1987;3:13-36.
22. Buschke H. Cued recall in amnesia. J Clin Neurophysiol. 1984;6:433-440.
23. Buschke H. Control of cognitive processing. In: Squire LR, Butters N, eds. Neuropsychology of Memory. New York, NY: Guilford Press; 1984:37-40.
24. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test. Boston, Mass: E Kaplan & H Goodglass; 1978.
25. Benton AL, Hamsher K, Varney NR, Spreen O. Contributions to Neuropsychological Assessment. New York, NY: Oxford University Press Inc; 1983.
26. Monsch AU, Bondi MW, Butters N, et al. A comparison of category and letter fluency in Alzheimer's disease and Huntington's disease. Neuropsychology. 1994;8:25-30.
FULL TEXT
27. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition. Washington, DC: American Psychiatric Association; 1987.
28. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan 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.
FREE FULL TEXT
29. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412-2414.
30. Berg L. Clinical Dementia Rating (CDR). Psychopharm Bull. 1988;24:637-639.
ISI
| PUBMED
31. Reisberg B, Ferris S, deLeon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry. 1982;130:1136-1139.
FREE FULL TEXT
32. Ivnik RJ, Malec JF, Smith GE, et al. Mayo's Older Americans Normative Studies: WAIS-R norms for ages 56 to 97. Clin Neuropsychol. 1992;6(suppl):1-30.
33. Ivnik RJ, Malec JF, Smith GE, et al. Mayo's Older Americans Normative Studies: WMS-R norms for ages 56 to 94. Clin Neuropsychol. 1992;6(suppl):49-82.
34. Ivnik RJ, Smith GE, Tangalos EG, Petersen RC, Kokmen E, Kurland LT. Wechsler Memory Scale (WMS): I.Q. dependent norms for persons ages 65-97 years: Psychological Assessment: J Consult Clin Psychol. 1991;3:156-161.
35. Ivnik RJ, Malec JF, Smith GE, Tangalos EG, Petersen RC. Neuropsychological tests' norms above age 55: COWAT, BNT, MAE Token, WRAT-R Reading, AMNART, STROOP, TMT and JLO. Clin Neuropsychol. 1996;10:262-278.
FULL TEXT
|
ISI
36. McGlone J, Gupta S, Humphrey D, Oppenheimer S, Mirsen T, Evans DR. Screening for early dementia using memory complaints from patients and relatives. Arch Neurol. 1990;47:1189-1193.
FREE FULL TEXT
37. Morris JC, Storandt M, McKeel DW, et al. Cerebral amyloid deposition and diffuse plaques in "normal" aging. Neurology. 1996;46:707-719.
FREE FULL TEXT
38. Tierney MC, Szalai JP, Snow WG, et al. Prediction of probable Alzheimer's disease in memory-impaired patients: a prospective longitudinal study. Neurology. 1996;46:661-665.
FREE FULL TEXT
39. Bowen J, Teri L, Kukull W, McCormick W, McCurry S, Larson E. Progression to dementia in patients with isolated memory loss. Lancet. 1997;349:763-765.
FULL TEXT
|
ISI
| PUBMED
40. Petersen RC, Smith GE, Kokmen E, Ivnik RJ, Tangalos EG. Memory function in normal aging. Neurology. 1992;42:396-401.
41. Jack CR, Petersen RC, Xu Y-C, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimer's disease. Neurology. 1997;49:786-794.
FREE FULL TEXT
42. Lemsky C, Chulune G, Ferman TJ, Ivnik RJ. Detecting clinically relevant memory changes in elderly patients. J Int Neuropsychol Soc. 1998;4:53.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter
What's this?
RELATED ARTICLE
Archives of Neurology Reader's Choice: Continuing Medical Education
Arch Neurol. 1999;56(3):370-371.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Clock Test Deficits Are Associated With Semantic Memory Impairment in Alzheimer Disease
Leyhe et al.
J Geriatr Psychiatry Neurol 2009;22:235-245.
ABSTRACT
Reduction of Basal Forebrain Cholinergic System Parallels Cognitive Impairment in Patients at High Risk of Developing Alzheimer's Disease
Grothe et al.
Cereb Cortex 2009;0:bhp232v1-bhp232.
ABSTRACT
| FULL TEXT
Predicting the time of conversion to MCI in the elderly: Role of verbal expression and learning
Oulhaj et al.
Neurology 2009;73:1436-1442.
ABSTRACT
| FULL TEXT
Association of White Matter Hyperintensity Measurements on Brain MR Imaging with Cognitive Status, Medial Temporal Atrophy, and Cardiovascular Risk Factors
Appel et al.
Am. J. Neuroradiol. 2009;30:1870-1876.
ABSTRACT
| FULL TEXT
Cognitive performance in community-dwelling English- and Spanish-speaking seniors
Federman et al.
Age Ageing 2009;38:669-675.
ABSTRACT
| FULL TEXT
Clinical Features in Early Parkinson Disease and Survival
Lo et al.
Arch Neurol 2009;66:1353-1358.
ABSTRACT
| FULL TEXT
Linking Hippocampal Structure and Function to Memory Performance in an Aging Population
Reitz et al.
Arch Neurol 2009;66:1385-1392.
ABSTRACT
| FULL TEXT
Differences in Brain Volume, Hippocampal Volume, Cerebrovascular Risk Factors, and Apolipoprotein E4 Among Mild Cognitive Impairment Subtypes
He et al.
Arch Neurol 2009;66:1393-1399.
ABSTRACT
| FULL TEXT
Potentially Inappropriate Medication Use in Older Adults With Mild Cognitive Impairment
Weston et al.
J Gerontol A Biol Sci Med Sci 2009;0:glp158v1-glp158.
ABSTRACT
| FULL TEXT
Cognitive Decline in Alzheimer's Disease Is Associated with Selective Changes in Calcineurin/NFAT Signaling
Abdul et al.
J. Neurosci. 2009;29:12957-12969.
ABSTRACT
| FULL TEXT
Regulatory Objectivity in Action: Mild Cognitive Impairment and the Collective Production of Uncertainty
Moreira et al.
Social Studies of Science 2009;39:665-690.
ABSTRACT
Computerized Cognitive Assessment of Mild Cognitive Impairment in Urban African Americans
Doniger et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2009;24:396-403.
ABSTRACT
White matter hyperintensities and medial temporal lobe atrophy in clinical subtypes of mild cognitive impairment: the DESCRIPA study
van de Pol et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:1069-1074.
ABSTRACT
| FULL TEXT
Declining financial capacity in mild cognitive impairment: A 1-year longitudinal study
Triebel et al.
Neurology 2009;73:928-934.
ABSTRACT
| FULL TEXT
Association of plasma amyloid {beta} with risk of dementia: The prospective Three-City Study
Lambert et al.
Neurology 2009;73:847-853.
ABSTRACT
| FULL TEXT
Impaired Category Fluency in Medial Temporal Lobe Amnesia: The Role of Episodic Memory
Greenberg et al.
J. Neurosci. 2009;29:10900-10908.
ABSTRACT
| FULL TEXT
The Indiana Faces in Places Test: Preliminary Findings on a New Visuospatial Memory Test in Patients with Mild Cognitive Impairment
Beglinger et al.
Arch Clin Neuropsychol 2009;24:607-618.
ABSTRACT
| FULL TEXT
CSF phosphorylated tau in the diagnosis and prognosis of mild cognitive impairment and Alzheimer's disease: a meta-analysis of 51 studies
Mitchell
J. Neurol. Neurosurg. Psychiatry 2009;80:966-975.
ABSTRACT
| FULL TEXT
The Clock Drawing Test--Modified and Integrated Approach (CDT-MIA) as an Instrument for Detecting Mild Cognitive Impairment in a Specialized Outpatient Setting
Heinik and Shaikewitz
J Geriatr Psychiatry Neurol 2009;22:171-180.
ABSTRACT
Progression of Mild Cognitive Impairment to Dementia in Clinic- vs Community-Based Cohorts
Farias et al.
Arch Neurol 2009;66:1151-1157.
ABSTRACT
| FULL TEXT
Relationship of Cerebrospinal Fluid Markers to 11C-PiB and 18F-FDDNP Binding
Tolboom et al.
JNM 2009;50:1464-1470.
ABSTRACT
| FULL TEXT
Subclinical cerebrovascular disease in mild cognitive impairment
Luchsinger et al.
Neurology 2009;73:450-456.
ABSTRACT
| FULL TEXT
Spanish Multicenter Normative Studies (NEURONORMA Project): Norms for the Rey-Osterrieth Complex Figure (Copy and Memory), and Free and Cued Selective Reminding Test
Pena-Casanova et al.
Arch Clin Neuropsychol 2009;0:acp041v1-acp041.
ABSTRACT
| FULL TEXT
Longitudinal progression of Alzheimer's-like patterns of atrophy in normal older adults: the SPARE-AD index
Davatzikos et al.
Brain 2009;132:2026-2035.
ABSTRACT
| FULL TEXT
Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve
Querbes et al.
Brain 2009;132:2036-2047.
ABSTRACT
| FULL TEXT
Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease
Desikan et al.
Brain 2009;132:2048-2057.
ABSTRACT
| FULL TEXT
Short Cognitive Performance Test: Diagnostic Accuracy and Education Bias in Older Brazilian Adults
Flaks et al.
Arch Clin Neuropsychol 2009;0:acp033v1-acp033.
ABSTRACT
| FULL TEXT
CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
Mattsson et al.
JAMA 2009;302:385-393.
ABSTRACT
| FULL TEXT
Use of Alzheimer Disease Biomarkers: Potentially Yes for Clinical Trials but Not Yet for Clinical Practice
Petersen and Trojanowski
JAMA 2009;302:436-437.
FULL TEXT
Longitudinal Modeling of Age-Related Memory Decline and the APOE {epsilon}4 Effect
Caselli et al.
NEJM 2009;361:255-263.
ABSTRACT
| FULL TEXT
Functional and cognitive criteria produce different rates of mild cognitive impairment and conversion to dementia
Saxton et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:737-743.
ABSTRACT
| FULL TEXT
Donepezil delays progression to AD in MCI subjects with depressive symptoms
Lu et al.
Neurology 2009;72:2115-2121.
ABSTRACT
| FULL TEXT
Stability of the Clinical Dementia Rating, 1979-2007
Williams et al.
Arch Neurol 2009;66:773-777.
ABSTRACT
| FULL TEXT
The Use of the Modified Telephone Interview for Cognitive Status (TICS-M) in the Detection of Amnestic Mild Cognitive Impairment
Cook et al.
J Geriatr Psychiatry Neurol 2009;22:103-109.
ABSTRACT
Eye Tracking During a Visual Paired Comparison Task as a Predictor of Early Dementia
Crutcher et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2009;24:258-266.
ABSTRACT
The Minute Hand Phenomenon in the Clock Test of Patients With Early Alzheimer Disease
Leyhe et al.
J Geriatr Psychiatry Neurol 2009;22:119-129.
ABSTRACT
Impaired Social Cognition in Mild Alzheimer Disease
Bediou et al.
J Geriatr Psychiatry Neurol 2009;22:130-140.
ABSTRACT
Making Physical Activity Accessible to Older Adults With Memory Loss: A Feasibility Study
Logsdon et al.
The Gerontologist 2009;49:S94-S99.
ABSTRACT
| FULL TEXT
Prosocial Capabilities in Alzheimer's Patients
Bosch-Domenech et al.
J Gerontol B Psychol Sci Soc Sci 2009;0:gbp034v1-gbp034.
ABSTRACT
| FULL TEXT
Cerebrospinal Fluid Biomarkers and Rate of Cognitive Decline in Very Mild Dementia of the Alzheimer Type
Snider et al.
Arch Neurol 2009;66:638-645.
ABSTRACT
| FULL TEXT
Cortical {alpha}7 Nicotinic Acetylcholine Receptor and {beta}-Amyloid Levels in Early Alzheimer Disease
Ikonomovic et al.
Arch Neurol 2009;66:646-651.
ABSTRACT
| FULL TEXT
Reviews: Current Concepts in Alzheimer's Disease: A Multidisciplinary Review
Minati et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2009;24:95-121.
ABSTRACT
Free Recall and Learning of Emotional Word Lists in Very Elderly People With and Without Dementia
Nieuwenhuis-Mark et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2009;24:155-162.
ABSTRACT
Progression of Mild Cognitive Impairment to Dementia: Contribution of Cerebrovascular Disease Compared With Medial Temporal Lobe Atrophy
Staekenborg et al.
Stroke 2009;40:1269-1274.
ABSTRACT
| FULL TEXT
Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN
Whitwell et al.
Neurology 2009;72:813-820.
ABSTRACT
| FULL TEXT
CSF APPs{alpha} and Phosphorylated Tau Protein Levels in Mild Cognitive Impairment and Dementia of Alzheimer's Type
Fellgiebel et al.
J Geriatr Psychiatry Neurol 2009;22:3-9.
ABSTRACT
Voxel-based analysis of cerebral glucose metabolism in mono- and dizygotic twins discordant for Alzheimer disease
Virta et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:259-266.
ABSTRACT
| FULL TEXT
Outcomes of Older Cognitively Impaired Individuals With Current and Past Depression in the NCODE Study
Steffens et al.
J Geriatr Psychiatry Neurol 2009;22:52-61.
ABSTRACT
Temporoparietal MR Imaging Measures of Atrophy in Subjects with Mild Cognitive Impairment That Predict Subsequent Diagnosis of Alzheimer Disease
Desikan et al.
Am. J. Neuroradiol. 2009;30:532-538.
ABSTRACT
| FULL TEXT
Alterations in Regional Brain Volume and Individual MRI-Guided Perfusion in Normal Control, Stable Mild Cognitive Impairment, and MCI-AD Converter
Huali Wang et al.
J Geriatr Psychiatry Neurol 2009;22:35-45.
ABSTRACT
The Metabolic Syndrome and Development of Cognitive Impairment Among Older Women
Yaffe et al.
Arch Neurol 2009;66:324-328.
ABSTRACT
| FULL TEXT
Fluorodeoxyglucose-Positron-Emission Tomography, Single-Photon Emission Tomography, and Structural MR Imaging for Prediction of Rapid Conversion to Alzheimer Disease in Patients with Mild Cognitive Impairment: A Meta-Analysis
Yuan et al.
Am. J. Neuroradiol. 2009;30:404-410.
ABSTRACT
| FULL TEXT
Mediterranean Diet and Mild Cognitive Impairment
Scarmeas et al.
Arch Neurol 2009;66:216-225.
ABSTRACT
| FULL TEXT
Detection of Alzheimer Pathology In Vivo Using Both 11C-PIB and 18F-FDDNP PET
Tolboom et al.
JNM 2009;50:191-197.
ABSTRACT
| FULL TEXT
MRI Biomarkers of Vascular Damage and Atrophy Predicting Mortality in a Memory Clinic Population
Henneman et al.
Stroke 2009;40:492-498.
ABSTRACT
| FULL TEXT
Alzheimer disease: Time to improve its diagnosis and treatment
SALLOWAY and CORREIA
Cleveland Clinic Journal of Medicine 2009;76:49-58.
ABSTRACT
| FULL TEXT
Diagnosis and Treatment of Dementia: 3. Mild Cognitive Impairment and Cognitive Impairment Without Dementia
Chertkow et al.
Focus 2009;7:64-78.
ABSTRACT
| FULL TEXT
A double-blind comparison of galantamine hydrobromide ER and placebo in Parkinson disease
Grace et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:18-23.
ABSTRACT
| FULL TEXT
Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease
Duara et al.
Neurology 2008;71:1986-1992.
ABSTRACT
| FULL TEXT
The Importance of Alzheimer Disease Assessment Scale-cognitive Part in Predicting Progress for Amnestic Mild Cognitive Impairment to Alzheimer Disease
Rozzini et al.
J Geriatr Psychiatry Neurol 2008;21:261-267.
ABSTRACT
Temporal trends in the long term risk of progression of mild cognitive impairment: a pooled analysis
Mitchell and Shiri-Feshki
J. Neurol. Neurosurg. Psychiatry 2008;79:1386-1391.
ABSTRACT
| FULL TEXT
The Impact of Caregiver Executive Skills on Reports of Patient Functioning
Dassel and Schmitt
Gerontologist 2008;48:781-792.
ABSTRACT
| FULL TEXT
Differentiation Between Dementia and Depression Among Older Persons: Can the Difference Between Actual and Premorbid Intelligence Be Useful?
Dierckx et al.
J Geriatr Psychiatry Neurol 2008;21:242-249.
ABSTRACT
Smoking and Cognitive Decline Among Middle-Aged Men and Women: The Doetinchem Cohort Study
Nooyens et al.
AJPH 2008;98:2244-2250.
ABSTRACT
| FULL TEXT
Increased Risk of Falling in Older Community-Dwelling Women With Mild Cognitive Impairment
Liu-Ambrose et al.
ptjournal 2008;88:1482-1491.
ABSTRACT
| FULL TEXT
Baseline differences between vascular cognitive impairment no dementia reverters and non-reverters
Williamson et al.
J. Neurol. Neurosurg. Psychiatry 2008;79:1208-1217.
ABSTRACT
| FULL TEXT
Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: Implication of Additional Loci
Lee et al.
Arch Neurol 2008;65:1518-1526.
ABSTRACT
| FULL TEXT
Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence
Garibotto et al.
Neurology 2008;71:1342-1349.
ABSTRACT
| FULL TEXT
A Behavioral Rehabilitation Intervention for Amnestic Mild Cognitive Impairment
Greenaway et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2008;23:451-461.
ABSTRACT
Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Normal Cognitive Aging: Population-Based Study
Geda et al.
Arch Gen Psychiatry 2008;65:1193-1198.
ABSTRACT
| FULL TEXT
MRI correlates of neurofibrillary tangle pathology at autopsy: A voxel-based morphometry study
Whitwell et al.
Neurology 2008;71:743-749.
ABSTRACT
| FULL TEXT
Risk profiles for mild cognitive impairment and progression to dementia are gender specific
Artero et al.
J. Neurol. Neurosurg. Psychiatry 2008;79:979-984.
ABSTRACT
| FULL TEXT
Within-Person Across-Neuropsychological Test Variability and Incident Dementia
Holtzer et al.
JAMA 2008;300:823-830.
ABSTRACT
| FULL TEXT
Cerebral Blood Flow by Using Pulsed Arterial Spin-Labeling in Elderly Subjects with White Matter Hyperintensities
Bastos-Leite et al.
Am. J. Neuroradiol. 2008;29:1296-1301.
ABSTRACT
| FULL TEXT
Elevated Cerebrospinal Fluid BACE1 Activity in Incipient Alzheimer Disease
Zetterberg et al.
Arch Neurol 2008;65:1102-1107.
ABSTRACT
| FULL TEXT
An aberrant protein complex in CSF as a biomarker of Alzheimer disease
Lovell et al.
Neurology 2008;70:2212-2218.
ABSTRACT
| FULL TEXT
Brief Screening for Mild Cognitive Impairment in Elderly Outpatient Clinic: Validation of the Korean Version of the Montreal Cognitive Assessment
Lee et al.
J Geriatr Psychiatry Neurol 2008;21:104-110.
ABSTRACT
Safety and efficacy of galantamine in subjects with mild cognitive impairment
Winblad et al.
Neurology 2008;70:2024-2035.
ABSTRACT
| FULL TEXT
Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia
Chertkow et al.
CMAJ 2008;178:1273-1285.
ABSTRACT
| FULL TEXT
Atrophy rates accelerate in amnestic mild cognitive impairment
Jack et al.
Neurology 2008;70:1740-1752.
ABSTRACT
| FULL TEXT
Patients with MCI and N400 or P600 abnormalities are at very high risk for conversion to dementia
Olichney et al.
Neurology 2008;70:1763-1770.
ABSTRACT
| FULL TEXT
Occurrence of cognitive impairment and dementia in the community: A 9-year-long prospective study
Caracciolo et al.
Neurology 2008;70:1778-1785.
ABSTRACT
| FULL TEXT
Amyloid-Associated Depression: A Prodromal Depression of Alzheimer Disease?
Sun et al.
Arch Gen Psychiatry 2008;65:542-550.
ABSTRACT
| FULL TEXT
The Japanese MCI Screen for Early Detection of Alzheimer's Disease and Related Disorders
Cho et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2008;23:162-166.
ABSTRACT
Comparability of the Clinical Diagnostic Criteria for Vascular Dementia: A Critical Review. Part I
Wiederkehr et al.
J. Neuropsychiatry Clin. Neurosi. 2008;20:150-161.
ABSTRACT
| FULL TEXT
Potential Role of Diffusion Tensor MRI in the Differential Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease
B. Parente et al.
Am. J. Roentgenol. 2008;190:1369-1374.
ABSTRACT
| FULL TEXT
Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial
van Uffelen et al.
Br. J. Sports. Med. 2008;42:344-351.
ABSTRACT
| FULL TEXT
Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults
Zimmerman et al.
Neurology 2008;70:1594-1600.
ABSTRACT
| FULL TEXT
A novel PSEN2 mutation associated with a peculiar phenotype
Piscopo et al.
Neurology 2008;70:1549-1554.
ABSTRACT
| FULL TEXT
A longitudinal study of drivers with Alzheimer disease
Ott et al.
Neurology 2008;70:1171-1178.
ABSTRACT
| FULL TEXT
Diagnosis and treatment of dementia: 2. Diagnosis
Feldman et al.
CMAJ 2008;178:825-836.
ABSTRACT
| FULL TEXT
The Prevalence of Dementia in an Urban Turkish Population
Gurvit et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2008;23:67-76.
ABSTRACT
|
