Diagnosis of Preclinical Alzheimer s Disease in a Clinical Setting

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1 International Psychogeriatrics, Vol. 13, No. 4, 2001, pp International Psychogeriatric Association Diagnosis of Preclinical Alzheimer s Disease in a Clinical Setting PIETER JELLE VISSER, FRANS R. J. VERHEY, RUDOLF W. H. M. PONDS, AND JELLEMER JOLLES ABSTRACT. Introduction. The aim of the study was to investigate whether the preclinical stage of Alzheimer s disease (AD) can be diagnosed in a clinical setting. To this end we investigated whether subjects with preclinical AD could be differentiated from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. Methods. Twenty-three subjects with preclinical AD, 44 subjects with nonprogressive mild cognitive impairment, and 25 subjects with very mild AD-type dementia were selected from a memory clinic population. Variables that were used to differentiate the groups were demographic variables, the Mini-Mental State Examination score, performance on cognitive tests, measures of functional impairment, and measures of noncognitive symptomatology. Results. Age and the scores for the delayed recall task could best discriminate between subjects with preclinical AD and subjects with nonprogressive mild cognitive impairment. The overall accuracy was 87%. The score on the Global Deterioration Scale and a measure of intelligence could best discriminate between subjects with preclinical AD and subjects with very mild AD-type dementia. The overall accuracy was 85%. Conclusions. Subjects with preclinical AD can be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild ADtype dementia, This means that preclinical AD is a diagnostic entity for which clinical criteria should be developed. KEYWORDS: Alzheimer s disease; preclinical Alzheimer s disease; dementia; mild cognitive impairment; follow-up studies; memory clinic The preclinical stage of Alzheimer s disease (AD) is a period in which subjects with AD have mild cognitive impairments but do not meet the criteria of dementia. The concept of preclinical AD has been derived from epidemiological studies. These studies showed that more than 10 years can pass between the onset of mild cognitive impairments and the diagnosis of dementia (Bondi et al., 1994; Elias et al., From the Department of Psychiatry and Neuropsychology, University of Maastricht, The Netherlands (P. J. Visser, MD, PhD; F. R. J. Verhey, MD, PhD; R. W. H. M. Ponds, PhD; and J. Jolles, PhD). 2000; Grober et al., 2000; Jacobs et al., 1995; Linn et al., 1995; Masur et al., 1994). There is agreat interest in the diagnosis of preclinical AD because it may allow treatment for AD to be started earlier. Treatment in the preclinical phase of AD may improve cognitive functioning and may slow the progression of the disease, which both will improve the quality of life. However, there is some skepticism about the Offprints. Requests for offprints should be directed to Pieter Jelle Visser, MD, PhD, Department of Psychiatry and Neuropsychology, University of Maastricht, PO Box 616, NL-6200 MD Maastricht, The Netherlands. pj.visser@np.unimaas.nl 41 1

2 412 diagnosis of preclinical AD in a clinical setting. Some clinicians feel that preclinical AD cannot be distinguished from mild dementia. In this view, subjects with a diagnosis of preclinical AD are in fact demented subjects. In addition, it may be difficult to distinguish subjects with preclinical AD from subjects who have mild cognitive impairment that is nonprogressive, and that is, for example, caused by normal aging or mild affective disorders. A major question therefore is whether preclinical AD is a diagnostic entity in a clinical setting. To answer this question we investigated to what extent subjects with preclinical ADcould be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia in the setting of a memory clinic. Subjects were considered to have preclinical AD if they were not demented at baseline but developed AD-type dementia after a 5-year follow-up. Subjects were considered to have nonprogressive mild cognitive impairment if they were neither demented at baseline nor after a 5-year follow-up. Variables that were used to differentiate between the groups were demographic variables, the score on the Mini-Mental State Examination (MMSE; Folstein et al., 1975), performance on cognitive tests, measures of functional impairment, and measures of noncognitive symptomatology. METHODS Subjects Subjects were selected from an outpatient memory clinic (Verhey et al., 1993). Subjects are referred to the memoryclinic by general practitioners (53%), neurologists (as%), or psychiatrists (19%). For P. J. Visser et al. the present study we included consecutive patients who were older than 55 years, had an MMSE score of at least 24, had no missing data for the Auditory Verbal Learning Task (see below), had no cognitive impairment in relation to any neurological disorder other than AD, any somatic disorder, or any major psychiatric disorder other than mild affective disorders, and had a baseline assessment before In order to identify subjects with nonprogressive mild cognitive impairment, preclinical AD, and very mild AD-type dementia, we used the following approach. First, we determined whether dementia was present at baseline. The clinical diagnosis of dementia was made according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994). If dementia was present, the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) criteria of probable AD were used to make the diagnosis of AD-type dementia (Mc- Khann et al., 1984). Subjects who were not demented at baseline were considered to have mild cognitive impairment and were reassessed after 5 years (Visser et al., 2000). If a subject met the DSM-IV criteria of dementia and the NINCDS-ADR- DA criteria of probable AD at the 5-year follow-up, the subject was considered to have preclinical AD at baseline. If a subject was not demented at the 5-year follow-up, the subject was considered to have nonprogressive mild cognitive impairment. The inclusion and exclusion criteria resulted in a sample of 44 subjects with nonprogressive mild cognitive impairment, 23 subjects with preclinical AD, and 25 subjects with very mild ADtype dementia (Table 1). International Psychogeriatrics, 13(4), December 2001

3 Preclinical AD in Clinical Setting Baseline and Follow-Up Assessment All subjects underwent a standardized baseline assessment that included a detailed history provided by the patient and a significant other, a psychiatric, neurological, and physical examination, laboratory tests for detecting hematological, liver, or kidney abnormalities, endocrine disorders or vitamin deficiencies that could cause cognitive impairment, a neuropsychological assessment (see below), and axial computed tomographic or magnetic resonance imaging, as described 413 elsewhere (Verheyet al., 1993). TheMMSE (Folstein et al., 1975) was used as a measure of global cognitive impairment. The functional impairment in activities of daily living was measured with the Global Deterioration Scale (GDS; Reisberg et al., 1982) and the first 11 items of the Blessed Dementia Rating Scale Part I (BDRS-COG; Blessed et al., 1968). Affective symptomatology and changes in personality and drive were measured with the Hamilton Depression Rating Scale-17 items (HDRS; Hamilton, 1960) and the last 10 items of the Blessed Dementia Rating Scale Part I TABLE 1. Baseline Characteristics Age, years Education, years Sex, male/female HDRS score GDS BDRS-COG score BDRS-PER score MMSE score MMSE, z score AVLT-IR, z score AVLT-LR, z score AVLT-DR, z score SCWT-card 1, z score SCWT-card 3, z score Fluency, z score IQ, z score Nonprogressive Very Mild Mild Alzheimer- Cognitive Preclinical Type Impairment AD Dementia Group I Group I1 Group I11 p Value (n = 44) (n = 23) (n = 25) I vs. I1 I1 vs. I (5.7) 10.1 (3.0) 24/ (6.0) (0.73) 0.86 (0.87) 28.6 (1.5) 0.22 (0.74) (0.86) (1.2) (1.3) (1.4) (0.95) (0.97) 0.11 (0.85) 70.1 (6.6) 10.8 (3.4) 11/ (5.6) (0.7) 1.0 (1.2) 26.9 (2.0) (1.0) (0.92) -1.6 (1.1) (1.0) (1.2) (1.6) (1.1) (0.88) 67.3 (7.4) 8.9 (2.1) 16/9 9.3 (5.9) (1.0) 1.7 (1.0) 25.6 (1.5) -1.1 (0.96) -1.3 (0.83) -2.4 (0.87) -2.2 (0.88) -1.8 (1.3) -3.0 (1.7) (0.7) (1.1) < oo < < <.001 Note All data are means (So> unless specified otherwise. z Scores are corrected for age, sex, and education. AD = Alzheimer s disease: GDS = Global Deterioration Scale; BDRS-COG = first 11 items of Blessed Dementia Rating Scale; BDRS-PER = last 10 items of Blessed Dementia Rating Scale; HDRS = Hamilton Depression Rating Scale; MMSE = Mini- Mental State Examination; AVLT-IR = immediate recall of Auditory Verbal Learning Test (AVLT); AVLT-LR = learning measure of AVLT; AVLT-DR = delayed recall of AVLT; SCWT = Stroop Color Word Test.

4 414 (BDRS-PER; Blessed et al., 1968), respectively. The diagnosis of dementiaand probable AD at baseline was made by a multidisciplinary team consisting of neuropsychiatrists, psychiatrists, residents in psychiatry and neurology, and neuropsychologists. The diagnosis of dementia was based on all available clinical information including the history of the patient and a significant other and did not depend on specific cutoff scores for cognitive tests or clinical rating scales. Subjects who were not demented at baseline were invited for a follow-up assessment after 5 years. The follow-up assessment consisted of a standardized questionnaire about medical history and cognitive complaints, the MMSE, the HDRS, and a neuropsychological test protocol (see below). If the subject refused to come for the follow-up assessment, a telephone interview was conducted that included a standardized questionnaire about medical history and cognitive complaints, and the Telephone Interview for Cognitive Status (n = 3) (Brandt et al., 1988). If the subject was unable to take part in the telephone interview, a significant other was contacted (n = 1). The diagnosis of dementia and probable AD at follow-up was made by a neuropsychiatrist and a neuropsychologist, who were unaware of the results of the baseline assessment. If there was disagreement about the clinical diagnosis, a consensus meeting was held, and if no agreement was reached the subject was considered not demented. Neuropsychological Assessment The neuropsychological assessment at baseline consisted of a series of standard clinical tests covering the cognitive domains of memory, language, executive functions and attention, and intelligence, P. J. Visser et al. as described elsewhere (Jolles, 1986; Verhey et al., 1993). We selected one test for each cognitive domain. Memory. Memory function was assessed with the Auditory Verbal Learning Test (AVLT; Brand & Jolles, 1985; Lezak, 1995). Fifteen words were presented five times and after each presentation the subject was asked to reproduce as manywords as possible. After 20 minutes, the delayed recall was tested. The variables selected for the study were the number of words memorized after the first presentation as a measure of immediate recall (AVLT-IR), the total number of words reproduced over the five trials as a measure of learning (AVLT-LR), and the number of words recalled after 20 minutes as a measure of delayed recall (AVLT-DR). Language. Verbal fluency was taken as a measure of language function. Fluency was defined here as the ability to name as many professions or trades as possible within 1 minute. Executive Functions/Atten tion. The Stroop Color Word Test (SCWT; Stroop, 1935) was taken as a measure of executive functions and attention. The test involves three cards that display 100 stimuli each: color names, colored patches, and color names printed in incongruously colored ink (Cards 1-3, respectively). We selected the time needed to read Card 1 or to name colors on Card 3. Subjects who completed Card 1 but who could not finish Card 3 were given the maximum score of the study population for Card 3. Intelligence. Intelligence was assessed with the Dutch version of the Wechsler Adult Intelligence Scale (n = 5) (Stinissen et al., 1970), the Groninger Intelligence Test (n = 75; Luteyn & van der Ploeg, 1983), or The Coloured Progressive Matrices (n = ll; Raven, 1965). Intelligence was not measured in one subject. International Psychogeriatrics, 13(4), December 2001

5 Preclinical AD in Clinical Setting All cognitive scores were corrected for age, sex, and education and expressed as z scores (Visser et al., 2000). The corrections were based on a reference population of 1,400 cognitively normal subjects older than 40 years randomly selected within age strata from a registry of general practitioners (Jolles et al., 1995; van Boxtel et al., 1998). The sign of the z scores of the SCWT Cards 1 and 3 was inverted such that a z score below zero indicated a below-average performance. Statistical Analysis Group comparisons with continuous variables were carried out with a f-test. The group differences in scores on the BDRS variables were analyzed with the Mann- Whitney test corrected for ties. Categorical data were analyzed with a chi-square test with continuity correction or the Mantel-Haenszel test for linear association. Logistic regression analysis with forward-step selection was performed to identify variables in a multivariate analysis that could best distinguish between subjects with preclinical AD and subjects with nonprogressive cognitive impairment, and between subjects with preclinical AD and very mild AD-type dementia. In order to limit the number of variables in the logistic regression analysis, we entered at the first step only those variables that were statistically significantly different (p value I.05) between the two groups in the univariate analysis. If two variables correlated more than.60 with each other, only the variable that could best differentiate between the diagnostic groups in the univariate test was entered. The diagnostic accuracy of the logistic regression models was presented as a receiver operating curve. We also calculated the sensitivity, specificity, positive 315 predictive value, and negative predictive value for preclinical AD in the case that subjects with a predicted probability for preclinical AD greater than.5 were considered to have preclinical AD according to the logistic regression model. Thus, the sensitivitywas the percentage of subjects with preclinical AD who had a predicted probability for preclinical AD greater than.5, the specificity was the percentage of subjects without preclinical AD who had a predicted probability for preclinical AD less than.5, the positive predictive value was the chance that subjects with a predicted probability for preclinical AD higher than.5 had preclinical AD, and the negative predictivevalue was the chance that subjects with a predicted probability for preclinical AD lower than 0.5 did not have preclinical AD. Step-forward discriminant analysis with principal component analysis was used to investigate the overlap between the three groups in a single analysis. Only those variables that were statisticallysignificantly different in the univariate analysis between subjects with preclinical AD and subjects with nonprogressive mild cognitive impairment or between subjects with preclinical AD and those with very mild AD-type dementia were entered in the first step. In order to include all subjects in the logistic regression and discriminant analyses, missing data (fluency n = 2, SCWT n = 2, Intelligence n = 1, BDRSPER or BDRS- COG n = 4) were substituted. The missing score was estimated from the other variables, except for the demographic variables. This estimate was based on a multiple regression analysis of data for the total study population. In this population, all neuropsychological variables were entered in the first step, and step-forward selection was used to select variables that were significantly associated with the

6 416 dependent variable. On the basis of the resulting model, an expected test score for each missing datum was calculated. Multivariate analyses were performed with and without substituted data. These models yielded similar results, and therefore data from the analyses with substituted data are presented. All statistical tests were two-tailed. The significance level was set at.05. RESULTS Distinction Between Subjects With Preclinical AD and Those With Nonprogressive Mild Cognitive Impairment Subjects with preclinical AD had a higher age at baseline, higher GDS scores, and lower scores on the MMSE, learning, delayed recall, SCWT Card 3, fluency, and the intelligence measure than did the subjects with nonprogressive mild cognitive impairment (Table 1). The cognitive profile of these subjects is shown in Figure 1. All variables that were statistically significantly different between the two groups in the univariate analysis were entered in the first step of the logistic regression analysis, except for the learning score, which had a high correlation with the delayed recall score (r =.76). The variables age and delayed recall score were retained in the model after forward-step selection. The sensitivity of the model was 74%, the specificity was 93%, the positive predictive value was 85%, and the negative predictive value was 87%. The overall accuracy was 87%. Figure 2 shows the receiver operating characteristic (ROC) curve of each predicted outcome probability. P. J. Visser et al. Distinction Between Subjects With Preclinical AD and Subjects With Very Mild Alzheimer-Type Dementia Subjects with preclinical AD had a higher education than subjects withverymild ADtype dementia and had lower scores on the GDS, BDRS-COG, and BDRSPER (Table 1). All cognitive measures except for the delayed recall measure were better in subjects with preclinical AD than they were in subjects with very mild AD-type dementia (Table 1). The cognitive profile of these subjects is shown in Figure 1. All variables that were statistically significantly different between the two groups in the univariate analysis were entered in the first step of the logistic regression analysis except for the immediate recall score, which was highly correlated with the SCWT Card 3 score (r = -.Sl). The variables GDS and intelligence were retained in the model after forwardstep selection. The sensitivity of the model for preclinical AD was 83%, the specificity was 88%, the positive predictive value was 86%, and negative predictive value was 85%. The overall accuracy was 85%. Figure 3 shows the ROC curve for each predicted outcome probability. We repeated the logistic regression analysis after exclusion of subjects with very mild AD-type dementia who had a GDS score of 4 at baseline. Again, the variables GDS and intelligence were retained in the model after forward-step selection. The sensitivity of the model for preclinical AD was 83%, the specificity was 83%, the positive predictivevaluewas 79%, the negative predictive value was 86%, and the overall accuracy was 83%. Discriminant Analysis The variables age, education, and scores for GDS, BDRS-COG, BDRS-PER, immediate recall, learning, delayed recall, SCWT International Psychogeriatrics, 13(4), December 2001

7 Preclinical AD in Clinical Setting AVLT-IR AVLT-LR AVLT-DR SCWT SCWT Fluency a me Card 1 Card 3 Figure 1. Profile of cognitive test performance (mean and standard error). Circles indicate the group with nonprogressive mild cognitive impairment (upper line), triangles indicate the group with preclinical Alzheimer s disease (middle line), and squares indicate the group with very mild AD-type dementia (lower line). AVLT-IR = immediate recall of Auditory Verbal Learning Test (AVLT); AVLT-LR = learning measure of AVLT; AVLT-DR = delayed recall of AVLT; SCWT= Stroop Color Word Test; IQ = intelligence quotient; MMSE = Mini-Mental State Examination. Cards 1 and 3, fluency, and intelligence were entered at the first step of the discriminant analysis. Stepwise selection selected the variables age and GDS, delayed recall, SCWT Card 3, and intelligence scores. On the basis of these variables, two discriminant canonical functions were constructed. The overall accuracy of these two functions for classifying the subjects in the groups was 84%. Of the subjects with nonprogressive mild cognitive impairment, 40 (91%) were correctly classified and 4 (9%) were misclassified as having preclinical AD. Of thesubjects with preclinical AD, 17 (74%) were correctly classified, 4 (17%) were misclassified as having nonprogressive mild cognitive impairment, and 2 (9%) were misclassified as having very mild AD-type dementia. Of the subjects with very mild AD-type dementia, 20 (80%) were correctly classified, 2 subjects (8%) were misclassified as having nonprogressive mild cognitive impairment, and 3 subjects (12%) were misclassified as having preclinical AD. The classification on the basis of the discriminant functions is shown in Figure 4. DISCUSSION The main finding of this clinical study is that subjects with preclinical AD can be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia.

8 418 P. J. Visser et al cn c I I 1 1 I I I I I I specificity Figure 2. Receiver operating characteristic curve of predicted probability for outcome for classifying subjects with preclinical Alzheimer s disease and subjects with nonprogressive mild cognitive impairment. Age and delayed recall performance were the most useful variables for distinguishing subjects with preclinical AD from subjects with nonprogressive mild cognitive impairment. This is consistent with previous studies (Devanand et al., 1997; Kluger et al., 1999; Petersen et al., 1995; Tierney et al., 1996). The time that is needed to obtain the delayed recall measure (25 minutes) may be too long in order to be used by a physician but it will be no problem as part of a neuropsychological assessment. The rating scales for noncognitive symptoms, i.e., the HDRS and BDRS- PER, were not of diagnostic value because noncognitive symptoms occurred as frequentlyin thesubjects with preclinical AD as in subjects with nonprogressive mild cognitive impairment. The diagnostic accuracy of the logistic regression model with age and delayed recall performance for detecting subjects with preclinical AD from among subjects with nonprogressive mild cognitive impairment was good and was comparable to that of other studies (Devanand et al., 1997; Kluger et al., 1999; Petersen et al., 1995; Tierney et al., 1996). The diagnostic accuracy may be further increased with measures of medial temporal lobe atrophy and the apolipoprotein E genotype (de Leon et al., 1993; Jack et al., 1999; Petersen et al., 1995; Visser et al., 1999, in press-a, in press-b). Subjects with preclinical AD could also be accurately distinguished from subjects with very mild AD-type dementia by the CDS score and the measure of intelligence. The little overlap suggests that it is unlikely International Psychogeriatrics, 13(4), December 2001

9 Preclinical AD in Clinical Setting ( I I I I I I I I I I specificity Figure 3. Receiver operating characteristic curve of predicted probability for outcome for classifying subjects with preclinical Alzheimer s disease and subjects with very mild AD-type dementia. that subjects with preclinical AD are in fact demented subjects who are misclassified as nondemented. The diagnostic accuracy may have been overestimated because the variables that were used to differentiate between the two groups in the multivariate analyses were also used for the dementia diagnosis at baseline. Note that this methodological flaw was unavoidable in the present study because there is no gold standard for the diagnosis of dementia other than the assessment of cognitive and functional impairment. This limitation was in part circumvented by making the diagnosis of dementia on the basis of all available clinical information and not on the basis of specific cutoff scores for cognitive tests or clinical rating scales. In addition, in order to limit the chance of circularity due to differences in GDS score at baseline, we repeated the logistic regression analysis after the exclusion of subjects with AD-type dementia who had a GDS score of 4. Because the degree of overlap between the groups in this analysis remained the same compared to the analysis that included all subjects, it is not likely that the little overlap between the groups is the result of circularity due to differences in GDS scores. The little overlap between the groups indicated that there is a consistent difference in cognitive and functional measures between subjects with preclinical AD and subjects with very mild AD-type dementia. Typically, the subjects with preclinical AD had less functional impairment, fewer changes in personality and drive as

10 420 P. J. Visser et al. Discriminant function 1 Figure 4. Classification according to discriminant analysis. Circles denote subjects with nonprogressive mild cognitive impairment; triangles denote subjects with preclinical Alzheimer s disease; squares denote subjects with very mild AD-type dementia. measured with the BDRS-PER, and fewer impairments in cognitive measures other than delayed recall performance than did the subjects with very mild AD-type dementia. The observation that the delayed recall performance was not significantly different between the subjects with preclinical AD and those with very mild ADtype dementia corroborates the observation that impairment of delayed recall performance is one of the first cognitive domains affected by AD (Almkvist et al., 1998; Foxet al., 1998; Newman et al., 1994; Nielsen et al., 1999; Small et al., 1997). Astrong point of the study was the long follow-up period of 5 years, which allowed an accurate diagnosis of preclinical AD and nonprogressive mild cognitive impairment. The clinicalsetting makes the results relevant to the clinician working in second-line care. The fact that only a few inclusion and exclusion criteriawere used improves the generalizability of the data. Alimitation of the study was the relatively large number of variables in the multivariate analysis in relation to the number of subjects, which may have led to overestimation of the diagnostic accuracy. However, only two variables were selected in the logistic regression analyses and five variables were selected in the discriminant analysis, which is acceptable (Lachenbruch, 1977). The diagnosis of subjects with nonprogressive mild cognitive impairment and subjects with preclinical AD was made according to the outcome at a 5- year follow-up period. The findings from the study may not apply if the diagnosis of International Psychogeriatrics, 13(4), December 2001

11 Preclinical AD in Clinical Setting the two groups is based on the outcome at longer follow-up intervals (Elias et al., 2000; Crober et al., 2000). The finding that the educational level was significantly higher in subjects with preclinical AD than it was in subjects withvery mild AD-type dementia may suggest that educational level confounded the distinction between the two groups. It is unlikely, however, that educational level has confounded the differences in cognitive scores because we corrected the cognitive scores for educational level; but it is possible that lowly educated subjects experience more functional impairment than highly educated subjects do and meet the criteria for dementia more easily, although this effect would be small given the small difference in educational level. We assessed depression with the HDRS and it may be possible that our results would have been slightly different if we had tested these depressive symptoms by a scale that is especially designed for usein elderlysubjects. Changes in personality and drive were tested with the BDRS-PER, which is a relatively crude measure for these symptoms. We might have found other results if we had used more specific scales for these noncognitive symptoms. We did not assess other noncognitive symptoms such as aggression and hallucinations. It is, however, unlikely that these other noncognitive symptoms would have had discriminative value because these symptoms are generally seen in more advanced stages of AD. In conclusion, the fact that subjects with preclinical AD could be accurately distinguished from subjects with nonprogressive mild cognitive impairment on the one hand and from subjects with very mild AD-type dementia on the other hand indicates that preclinical AD is a diagnostic entity. Criteria for preclinical AD should therefore be developed. REFERENCES 421 Almkvist, O., Basun, H., Backman, L., Herlitz, A., Lannfelt, L., et al. (1998). Mild cognitive impairment-an early stage of Alzheimer s disease? Journal of Neural Transmission, 54(Suppl.), American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. Blessed, G., Tomlinson, B. E., & Roth, M. (1968). The association between quantitative measures of dementia and of senile changes in the cerebral grey matter of elderly subjects. British Journal ofpsychiatry, 114, Bondi, M. W., Monsch, A. U., Galasko, D., Butters, N., Salmon, D. P., et al. (1994). Preclinical cognitive markers of dementia of the Alzheimer type. Neuropsychology, 8, Brand, N., & Jolles, J. (1985). Learning and retrieval rates of words presented auditorily and visually. Journal of Generul Psychology, 112, Brandt, J., Spencer, M., &Folstein, M. (1988). The Telephone Interview for Cognitive Status. Neuropsychiatry, Neuropsychology and Behavioral Neurology, 1, de Leon, M. J., George, A. E., Convit, A., Tarshish, C. Y., McRae, T., et al. (1993). The radiologic prediction of Alzheimer disease: The atrophic hippocampal formation. American Journal of Neuroradiology, 14, Devanand, D. P., Folz, M., Gorlyn, M., Moeller, J. R., & Stern, Y. (1997). Questionable dementia: Clinical course and predictors of outcome. Journal of the American Geriatrics SocieQ, 45, Elias, M. F., Beiser, A., Wolf, P. A., Rhoda, A., White, R. F., et al. (2000). The preclinical phase of Alzheimer s disease. A 22-year prospective study of the Framingham cohort. Archives of Neurology, 57, Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). Mini-Mental State : A practical

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