Cognitive Status, Depressive Symptoms, and Health Status as Predictors of Functional Disability Among Elderly Persons With Low-to-Moderate Education: The Faenza Community Aging Study

Cognitive Status, Depressive Symptoms, and Health Status as Predictors of Functional Disability Among Elderly Persons With Low-to-Moderate Education The Faenza Community Aging Study Diana De Ronchi, M.D., Ph.D., Francesca Bellini, M.D. Domenico Berardi, M.D., Alessandro Serretti, M.D. Barbara Ferrari, Ph.D., Edoardo Dalmonte, M.D.

Objective: The authors examined the impact of very early dementia and symptoms of depression on functional disability in a community-based group of 216 elderly people with low-to-moderate education level. Methods: The combined effect of very early dementia and symptoms of depression on functional disability was assessed with a logistic-regression model in which functional disability was the dependent variable. The same model was repeated with each item on the Instrumental Activities of Daily Living scale as the dependent variable. Results: Very early dementia alone was strongly associated with functional disability, and this association tripled in subjects with both very early dementia and symptoms of depression. In fact, whereas subjects with very early dementia had an 11-fold higher risk than normal persons for disability, subjects with both very early dementia and symptoms of depression showed a 37-fold higher risk for functional dependence. Conclusions: Elderly people who suffer from very early dementia and who also have symptoms of depression are at very high risk for functional disability and have a great need for accurate diagnostic assessment. If confirmed, the results are relevant for prevention because people who suffer from very early dementia and have symptoms of depression may be a suitable target group for intervention before the development of severe disability. (Am J Geriatr Psychiatry 2005; 13:672–685)

Received November 13, 2003; revised July 20, 2004, and January 13, 2005; accepted January 18, 2005. From the Institute of Psychiatry, Univ. of Bologna, Bologna, Italy (DDR, FB, DB, BF); the Dept. of Psychiatry, Vita-Salute Univ., San Raffaele Institute, Milan, Italy (AS); the Dept. of Geriatric Medicine, Azienda SL Ravenna, Faenza, Italy (ED). Send correspondence and reprint requests to Diana De Ronchi, M.D., Institute of Psychiatry, Univ. of Bologna, Viale Carlo Pepoli 5, 40123 Bologna, Italy. e-mail: [email protected] 䉷 2005 American Association for Geriatric Psychiatry

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De Ronchi et al.

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unctional disability in elderly persons, and the institutionalization that often follows, is a major public health concern in developed countries, resulting in high expenditures at both the individual and community levels. Dementia1 and late-life depression2–6 are major causes of functional disability in elderly persons, with a mutually reinforcing relationship.7 Recently, the very early clinical phases of dementia have become an area of particular research interest8 because even early in the dementia process, patients can experience changes in higher-level functions, such as the ability to travel or manage complex activities.9 The investigation of the very early clinical phases of dementia is worthwhile because very early dementia is a common condition in elderly persons.10 Moreover, longitudinal studies show that, in 35% of individuals with mild cognitive impairment, nodementia progressed to dementia over 3 years,11 and that early recognition of very early dementia allows early access to potentially therapeutic intervention.12 Some studies have found that depression is a risk factor for the development of cognitive decline,13–18 whereas others could not confirm this finding.19–22 Examination of both directions of the relationship between depression and cognitive impairment shows that depression in old age seems to be a concomitant phenomenon of cognitive impairment, rather than an independent risk factor.23,24 Available data on the relationship between the very early clinical phases of dementia, depression, and disability, are mostly derived from clinically-based observations on elderly subjects who are almost cognitively intact.25–27 To our knowledge, no studies have specifically investigated individuals with a Mini-Mental State Exam (MMSE)28 score lower than 23, which is the threshold used to define cognitively impaired subjects,11 also taking into account mild deficits in higher-level functions that are very sensitive to early dementia. Therefore, our understanding of the relationship between the very early clinical phases of dementia, depression, and disability remains far from complete. The aim of this study was to evaluate the impact of very early dementia and symptoms of depression on functional disability in elderly persons. The investigation of this relationship is relevant for preventing or delaying disability among elderly persons. Data on cognitive impairment and dementia were gathered from the Faenza Project (northern Italy), from a community-based group of elderly people.

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METHODS Population Study The Faenza Project is a population-based study specifically designed to investigate aging and dementia in elderly people living in Faenza, northern Italy. Baseline data collection and first ascertainment of cases were done in 1992–1993 by means of a door-todoor survey using a two-phase design (Table 1). Between 1995 and 1996, a follow-up, including a clinical and psychological examination, was carried out on a random sample of the inhabitants of the Old Town district of Faenza who were born between 1911 and 1929 and who underwent the first ascertainment of cases in 1992–1993. (Detailed information of time schedule and design are reported in Table 1.) The present study reports the data collected in 1995–1996 on depression and disability in relation to dementia and very early dementia. Information on cognitive status, collected in 1992–1993, were used in the present study to objectively document any cognitive decline during the follow-up period of 3 years, in order to assess whether the very early dementia subjects actually had a progressive cognitive decline or were merely stably low-functioning. Information on gender, education, and main occupation during life, collected in 1992–1993, were also used in the present study. Briefly, the population study for the current analysis consisted of 216 elderly subjects, who lived in the Old Town district of Faenza. Of 1,472 participants who lived in the Old Town district of Faenza at the first clinical assessment (1992–1993), 263 (17.9%) subjects died before 1995. Of the remaining subjects (N⳱1,209), a stratified random sample of residents who were born between 1911 and 1929 was drawn. Strata were defined according to age-group (people who were born in Years 1927–1929, 1922–1926, 1917– 1921, 1912–1916, and 1911) and sex. The sampling ratio was chosen so as to allow sufficient numbers of subjects in each group: 20% for women born in 1927– 1929, 1922–1926, 1917–1921, and 1912–1916, and 20% for men born in 1927–1929 and 1922–1926. The sampling ratio was 30% for women born in 1911, and for men born in 1917–1921 and 1912–1916. Finally, the sampling ratio was 40% for men born in 1912–1916 and in 1911. In total, 284 subjects were asked to participate in this phase; 68 individuals (23.9%) denied

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Prediction of Functional Disability their consent; thus, 216 (76.1%) ultimately were clinically examined. Study Model The participants first received a letter from their own general practitioner, and then were contacted by telephone in order to obtain consent and book the first visit. All participants were examined at their home by two physicians following a standardized protocol, including a social and medical interview, neuropsychological tests, and a clinical examination. Data were obtained 1) directly from subjects having an MMSE score ⱖ23, and 2) from informants, who usually were close relatives, for subjects with MMSE ⬍23. All the subjects underwent a standard Italian version of the MMSE,28 which used the word carne (meat) for backward spelling. As did Grigoletto et al.,29 we required both the serial subtraction item and the backward spelling item. Of the two items, we used the one giving the highest score. To standardize assessments and diagnoses, detailed protocols were TABLE 1.

developed, together with training materials for the physicians. The physicians had at least 4 years’ experience in the cognitive evaluation of elderly people. A further training of the two physicians by the Faenza Project experts (DDR, ED) in applying the protocol and tests was carried out (approximately 2 days). Interrater reliability for MMSE was tested in 10 subjects of our sample, with one psychiatrist conducting the interview and the other two rating it simultaneously. Intraclass correlation coefficient (ICC) for the MMSE indicated excellent interrater reliability (ICC⳱0.997; 95% confidence interval [CI]: 0.987– 0.999; p ⬍0.001). For MMSE test–retest reliability, one of the two physicians examined the same 10 persons on the next day (ICC⳱0.989; 95% CI: 0.801–0.998; p ⬍0.001). The same physicians also administered the Global Deterioration Scale,30 the Geriatric Depression Scale (GDS),31 the Hachinski Ischemic Score,32 and the Instrumental Activities of Daily Living (IADL) assessment.33 The cognitive profile also included the Blessed Dementia Scale, incorporating the Informa-

Scheme of Time Schedule and Design of The Faenza Project

Calendar Years

Study Population

Type of Contact and Data Collection

Time 1 1992–1993

Faenza population, including the Old Town District of Faenza population age 61Ⳮ (7,930 subjects)

Baseline data collection Phase I: MMSE, Global Deterioration Scale, HIS, social interview, medical history, and clinical examination Phase II: clinical and psychological examination

Time 2 1995–1996, present study

Stratified for age and gender, random sample of the Old Town District of Faenza population 65–84 years old (216 subjects)

Follow-up (3 years) In all: MMSE, Global Deterioration Scale, Geriatric Depression Scale, IADL, HIS, clinical and psychological examination, social interview, cognitive tests: CAMCOG items (impairment in A: short-term memory; B: long-term memory; C: abstract thinking; D: judgment; E: other disturbances in higher cortical functions), Blessed Dementia Scale (incorporating the IM-C Test and the Dementia Scale)

Subjects Examined By Phase I: All subjects interviewed by: 1) two nurses, who administered the MMSE and a structured questionnaire, including a social interview; 2) two physicians, who administered the Global Deterioration Scale, collected medical history, and assessed physical health Phase II: Persons with MMSE ⱕ28 and/or Global Deterioration Scale ⱖ2 were clinically examined in Phase II by physicians All subjects were interviewed, clinically and psychologically examined by two physicians, who also collected detailed data on symptoms of depression and functional disability

Note: MMSE: Mini-Mental State Exam; HIS: Hachinski Ischemic Score; IADL: Instrumental Activities of Daily Living; IMC: InformationMemory-Concentration.

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De Ronchi et al. tion-Memory-Concentration (IMC) Test and the Dementia Scale,34 and the items evaluating any impairment in 1) short-term memory; 2) long-term memory; 3) abstract thinking; 4) judgment; and 5) other disturbances in higher cortical functions, from the Cambridge Examination for Mental Disorders of Elderly Persons (CAMDEX),35 corresponding to the DSM-III-R criteria for dementia.36 Physical health was assessed by the physician during the clinical examination and with the support of next-of-kin interview, if necessary. Physical diagnoses were made according to the International Classification of Diseases–9th Revision (ICD-9). Written informed consent was obtained after the procedures had been fully explained to all subjects. In the case of deceased subjects, medical records and death certificates were also reviewed. The study was approved by the Ethical Committee of the Local Health Authority of Ravenna, Ravenna, Italy. Diagnosis of Dementia The diagnostic criteria and procedures applied to all 216 participants in order to reach the clinical diagnosis of dementia were the following (Figure 1): in Step 1, a preliminary diagnosis was made after a discussion among the physicians who had examined the participant. There were 19 discordant cases (8.8%) out FIGURE 1.

of 216. The ICC for the preliminary diagnoses given by the two physicians was 0.82; 95% CI: 0.77–0.86; p ⬍0.001. Step 2 involved a second preliminary diagnosis of all participants by a psychiatrist with expertise in dementia. In Step 3, the two preliminary diagnoses were compared, and cases with discordant diagnoses were reviewed again to ascertain causes of agreement and disagreement. This process eliminated most of the discordant diagnoses. However, in those cases in which disagreement persisted, a supervising geriatrician made the final diagnosis. This process yielded a diagnosis of the presence or absence of dementia according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised (DSM-III-R).37 Diagnosis of Very Early Dementia During the diagnostic process, the functional performance, a core feature of a clinical diagnosis of dementia, was carefully evaluated among all the participants after we reviewed the available clinical data gathered from subjects and close relatives. The investigators in this study judged the subjects diagnosed with very early dementia to suffer from cognitive impairment and mild deficits in higher-level functions, such as the ability to travel or manage complex activities.9,38,39 Cognitive impairment, per se, was defined

Diagnostic Procedure and Discrepant Cases

Discrepant Cases after the two preliminary diagnoses 19 Cases (8.8%) of 216

Dementia/No Dementia 3 Cases

Very Early Dementia/Dementia 9 Cases

Very Early Dementia/No Dementia 7 Cases Initial Review

3 Dementia Cases 0 Discrepant Cases

2 Very Early Dementia Cases 1 Dementia Case 6 Discrepant Cases

6 Very Early Dementia Cases 1 No Dementia Case 0 Discrepant Cases Final Review

3 Very Early Dementia Cases 3 Dementia Cases

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Prediction of Functional Disability on the basis of the MMSE performance. The effects of age and education on the MMSE score were taken into account because the definition of cognitive impairment was based on age- and education-adjusted norms. On the basis of a previous report,40 we used four education categories: (0–4, 5–7, 8–12, and 13–17 years of schooling), and four age strata were defined (65–69, 70–74, 75–79, and 80–84 years of age). A subject was classified as cognitively impaired if he or she did not have dementia but scored 1 standard deviation (SD) below the age- and education-specific mean on the MMSE calculated for non-dementia subjects. Cut-off points on the MMSE increased with decreasing age and were higher for persons with more years of education. Cut-off levels for cognitive impairment ranged from 21, for persons over age 80 years with no or very low education level, to 26, for individuals with high education levels, in the 65–69-year age category. Persons scoring lower than these cut-off points on the MMSE were classified as cognitively impaired. Furthermore, the information on cognitive and functional decline collected in 1992–1993 was used in the present study to objectively document any cognitive and functional decline during the follow-up period of 3 years, in order to assess whether the veryearly-dementia subjects actually had a progressive cognitive decline or were merely low-functioning. Symptoms of Depression Symptoms of depression were assessed by two physicians with the Geriatric Depression Scale (GDS),31 a 30-item scale that has been shown to be useful in distinguishing elderly depressed subjects from elderly normal subjects. According to Yesavage and colleagues, a score of 0–10 should be considered normal, and ⱖ11 is indicative of depression. The GDS correlated well with the number of research diagnostic criteria symptoms for depression; in fact, the sensitivity and specificity of the GDS had been demonstrated in a previous study,41 and a cut-off of 11 had an 84% sensitivity and 95% specificity level. Functional Status Functional status was measured in terms of ability to perform the Instrumental Activities of Daily Living (IADL).33 The IADL deals with the execution of complicated tasks that have a broad impact in linking social competency and independent living. The IADL

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items used in this study provide information about the subject’s ability to use the telephone, shop, travel, take medications, and manage money. Information on IADL performance was obtained 1) directly from subjects having an MMSE score ⱖ23; and 2) from close relatives, for subjects with an MMSE score ⬍23. Any difficulty in the performance of these activities was recorded as “dependence” in the corresponding item. Disability was defined as the need for assistance in two or more activities on the IADL. Because environmental conditions or gender roles due to traditional norms might reduce the opportunity to perform a certain activity, items for which the person may lack opportunity or experience (e.g., if a person’s spouse always took responsibility for balancing the checkbook or paying the bills) were recorded as absent on the IADL scale. Statistical Analysis The association among putative risk factors and cognitive status was analyzed by using odds ratios (ORs) with Wald’s chi-square test from logisticregression models. Different logistic-regression models were performed by using very-early-dementia and dementia as a dependent variable dichotomized into Present/Absent. Independent variables were entered into the models as follows: 1) age as a continuous variable (1-year increase) and as a dichotomous variable (65–74 versus 75–84 years); 2) symptoms of depression as a dichotomous variable (Present versus Absent) and as a continuous variable (1- and 5-point increase on the GDS); 3) gender (men versus women); 4) years of education, as a continuous variable (1-year increase). The combined effect of very early dementia and symptoms of depression on functional disability was assessed by a logistic-regression model in which functional disability was the dependent variable. Very early dementia and symptoms of depression were combined as an indicator variable upon the presence/absence of these two conditions, whereas being cognitively normal without symptoms of depression was the reference group. Other groups were the following: being cognitively normal with symptoms of depression; having very early dementia without symptoms of depression; and having very early dementia with symptoms of depression. The same logistic-regression model was repeated using each item on the IADL scale as a dependent variable, in-

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De Ronchi et al. stead of IADL disability. Additional models were used to verify the possible confounding effect of cardio- and cerebrovascular diseases, fractures and osteoarticular diseases, and malignancy on functional disability. In order to account for the stratification pattern in our analyses, the stratification variables were also introduced as covariates into all the models. The ICC42 has been used to evaluate interrater reliability and test–retest reliability of the MMSE and the interrater reliability of diagnosis of dementia and very-early-dementia given by the two physicians. Data were analyzed with the Statistical Package for the Social Sciences (SPSS) for Windows.

RESULTS Of the 1,472 participants in the first clinical assessment, carried out in 1992–1993, 263 subjects died before undergoing the examination (1995–1996). Of the remaining subjects (N⳱1,209), a stratified random sample (N⳱284) was asked to participate. Sixty-eight individuals (23.9%) denied their consent; thus, 216 (76.1%) ultimately received clinical examinations. Deceased Subjects Results of a logistic-regression model in which being deceased was the dependent variable showed that the deceased subjects more frequently had dementia (OR⳱3.3; 95% CI: 1.3–8.9; Wald v2[1]⳱5.8; p⳱0.016), were men (OR⳱1.78; 95% CI: 1.35–2.35; Wald v2[1]⳱16.5; p ⬍0.001), and were older (OR⳱ 1.07; 95% CI: 1.04–1.09; Wald v2[1]⳱24.1; p ⬍0.001 for an increment of 1 year of age) than the other participants. No significant differences were found between deceased subjects and participants in relation to veryearly-dementia diagnosis and years of education. Refusals Results of a logistic-regression model, in which being a “refusal” was the dependent variable, showed that the subjects who refused to participate in the study more frequently had dementia (OR⳱4.6; 95% CI: 1.2–17.1; Wald v2[1]⳱5.1; p⳱0.023) and had more education (OR⳱1.07; 95% CI: 1.02–1.13; Wald v2[1]⳱7.4; p⳱0.006 for an increment of 1 year of education) than the participants. No significant differ-

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ences were found between refusals and participants in relation to very-early-dementia diagnosis, age, and gender. Our population study consisted of 216 elderly subjects: 19 with dementia, 23 with very early dementia, and 174 cognitively normal subjects (Table 2). The mean age and years of education (SD) were 75.3 (5.7) and 6.1 (4.4), respectively. The mean MMSE scores (SD) were 14.9 (8.3) in dementia, 19.4 (3.6) in very early dementia, and 27.4 (2.0) in normal subjects. Significant differences were found among all three groups. Cognitively normal elderly people proved to have a higher level of education, to be more frequently white-collar workers, to have less IADL disability, and to be less frequently depressed than elderly persons with very early dementia. Subjects with very early dementia had less IADL disability and were less frequently depressed than elderly persons with dementia. The majority of the subjects had at least one physical disease, with no significant differences between normal subjects, subjects with very early dementia, and subjects with dementia. The data regarding functional dependence in normal subjects, subjects with dementia, and those with very early dementia, in terms of individual items of IADL, are presented in Figure 2. Significant differences in prevalence of dysfunction in individual items were found among all the three groups: ability to use the telephone: v2[2]⳱23.4; p ⬍0.001; shopping: v2[2]⳱64.9; p ⬍0.001; mode of transportation: v2[2]⳱ 76.0; p ⬍0.001; responsibility for own medications: v2[2]⳱103.1; p ⬍0.001; ability to handle finances: v2[2]⳱103.1; p ⬍0.001. Subjects with dementia had the highest prevalence of dysfunction in all IADL activities, and those with very early dementia had higher prevalence than normal subjects in all IADL activities. The distribution of dysfunction was similar among the three groups, with shopping being the most affected item, and ability to use the telephone the least affected item for all subjects. Considering all participants, the prevalence of symptoms of depression, defined by a score above 10 on the GDS, was 43.1 per 100 (95% CI: 36.4–49.8). The prevalence of symptoms of depression was higher in people with dementia and very early dementia, and in the eldest group (51.4 per 100; 95% CI: 42.1–60.6), as compared with the youngest group (34.0 per 100; 95% CI: 24.7–43.3), with no gender difference for age. The study also focused on the association of symp-

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678 Dementiab (Nⴔ19) 75 (43.1) 99 (56.9)

Normalb (Nⴔ174)

89 (51.1) 85 (48.9) 17 (9.8) 32 (18.4) 26 (14.9) 33 (19.0) 37 (21.3) 24 (13.8) 0.2 (0.6) 7 (4.0) 100 (57.5) 46 (26.4) 4 (2.3) 9.4 (5.7) 60 (34.5)

13 (56.5) 10 (43.5) 5 (21.7) 9 (39.1) 6 (26.1) 1 (4.3) 0 (0.0) 2 (8.7) 1.2 (1.9) 7 (30.4) 14 (60.9) 3 (13.0) 1 (4.3) 14.2 (6.3) 16 (69.6)

v2[1]⳱2.4, p⳱0.125

v2[2]⳱5.4, p⳱0.068

F⳱27.6, p ⬍0.001 v2[2]⳱31.4, p ⬍0.001

t ⳱ –2.8, p⳱0.008 v2[1]⳱5.6, p⳱0.018

v2[2]⳱0.8, p⳱0.659 v2[1]⳱0.3, p⳱0.611 v2[2]⳱3.2, p⳱0.203 v2[1]⳱3.2, p⳱0.071 v2[2]⳱0.8, p⳱0.673 v2[1]⳱0.02, p⳱0.890

F⳱105.1, p ⬍0.001 t ⳱ –4.1, p ⬍0.001 v2[2]⳱106.6, p ⬍0.001 v2[1]⳱14.8, p ⬍0.001

v2[5]⳱4.6, p⳱0.473

t ⳱ –1.7, p⳱0.107 v2[2]⳱3.1, p⳱0.209

F⳱10.1, p ⬍0.001 v2[4]⳱23.0, p ⬍0.001

v2[10]⳱21.8, p⳱0.016

t ⳱ –1.8, p⳱0.081 v2[1]⳱1.0, p⳱0.327

v2[5]⳱8.1, p⳱0.152

v2[1]⳱5.3, p⳱0.021

t⳱2.1, p⳱0.036 v2[2]⳱4.8, p⳱0.092

t ⳱ –3.4, p⳱0.001 v2[1]⳱6.2, p⳱0.013

v2[1]⳱0.9, p⳱0.334

Dementia Versus Normal

t ⳱ –3.8, p ⬍0.001 v2[1]⳱10.4, p ⬍0.001

v2[1]⳱0.8, p⳱0.779 v2[1]⳱1.9, p⳱0.163 v2[1]⳱0.3, p⳱0.557

t ⳱ –6.8, p ⬍0.001 v2[1]⳱24.6, p ⬍0.001

v2[1]⳱0.8, p⳱0.372 v2[1]⳱0.9, p⳱0.335 v2[1]⳱0.6, p⳱0.440

t ⳱ –5.1, p ⬍0.001 t ⳱ –17.9, p ⬍0.001 v2[1]⳱21.3, p ⬍0.001 v2[1]⳱114.2, p ⬍0.001

v2[5]⳱15.8, p⳱0.007

v2[1]⳱0.2, p⳱0.628

t⳱4.1, p ⬍0.001 v2[2]⳱20.3, p ⬍0.001

t ⳱ –0.9, p⳱0.351 v2[1]⳱2.2, p⳱0.140

v2[1]⳱0.6, p⳱0.429 v2[1]⳱0.001, p⳱0.973

Very Early Dementia Versus Normal

Univariate Analyses Dementia Versus Very Early Dementia

F⳱5.8, p⳱0.003 v2[2]⳱7.7, p⳱0.021

v2[2]⳱1.0, p⳱0.621

Overall Group Differences

Note: aVariable was evaluated at Time 1 (1992–1993); bVariable was evaluated at Time 2 (1995–1996). Dementiab: MMSE mean (standard deviation): 14.9 (8.3); Very Early Dementiab: 19.4 (3.6); Normalb: 27.4 (2.0). The following variables have missing values: occupation (N⳱5); IADL disability (N⳱1); symptoms of depression (N⳱5). Disability was defined as need for assistance in two or more activities on the IADL. Depression was scored as GDS ⬎10. SD: standard deviation; MMSE: Mini-Mental State Exam, adjusted for age and education; IADL: Instrumental Activities of Daily Living; GDS: Geriatric Depression Scale.

6.7 (4.4) 53 (30.5) 57 (32.8) 64 (36.8)

2.8 (3.2) 18 (78.3) 3 (13.0) 2 (8.7)

76.0 (6.2) 74.8 (5.4) 8 (34.8) 89 (51.1) 15 (65.2) 85 (48.9)

10 (43.5) 13 (56.5)

Very Early Dementiab (Nⴔ23)

Demographic and Clinical Characteristics of the Study Population

Gender (N, %)a Men 6 (31.6) Women 13 (68.4) Age-groups, years b Mean (SD) 79.3 (5.9) 65–74 years (N, %) 4 (21.1) 75–84 years (N, %) 15 (78.9) Education, years a Mean (SD) 4.5 (3.5) 0–3 (N, %) 10 (52.6) 4–5 (N, %) 6 (31.6) 6Ⳮ (N, %) 3 (15.8) b Marital status (N, %) Unmarried, widowed, divorced 15 (78.9) Married 4 (21.1) Main occupation during working lifea (N, %) Farmer 3 (15.8) Factory worker 8 (42.1) Homemaker/retired 3 (15.8) White-collar worker 1 (5.3) Craftsman/shopkeeper 3 (15.8) Other 1 (5.3) IADL disabilityb Mean (SD) 3.3 (1.4) Disability (N, %) 17 (89.5) Health statusb (N, %) Cardio- and cerebrovascular disease 13 (68.4) Fractures and osteoarticular disease 7 (36.8) Malignancy 1 (5.3) Symptoms of depressionb Mean (SD) 19.7 (5.4) Depressive symptoms (N, %) 15 (78.9)

TABLE 2.

Prediction of Functional Disability

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De Ronchi et al. toms of depression and functional dependence, adjusted for age, gender, and years of schooling. The GDS score (1-point increase) was positively associated with functional disability (OR⳱1.16; 95% CI: 1.08–1.24; Wald v2[1]⳱16.7; p ⬍0.001). Elderly persons with symptoms of depression were more frequently disabled than those without symptoms of depression (23.1% versus 5.0%; v2[1]⳱15.0; p ⬍0.001), both in the eldest group (28.1% versus 11.1%; v2[1]⳱5.0; p⳱ 0.025) and in the youngest one (14.7% versus 0; v2[2]⳱10.1; p⳱0.002). The data regarding functional disability, in terms of individual items on the IADL, in elderly people with and without symptoms of depression, are presented in Figure 3. Significant differences in the prevalence of dysfunction in individual items were found among elderly persons with and without depressive symptoms: elderly persons with symptoms of depression had the highest prevalence of dysfunction in shopping, traveling, taking medications, and managing money (ability to use the telephone: v2[1]⳱0.7; p⳱0.4; shopping: v2[1]⳱9.6; p⳱ 0.002; mode of transportation: v2[1]⳱11.1; p⳱0.001; responsibility for own medications: v2[1]⳱10.3; p⳱ 0.001; ability to handle finances: v2[1]⳱10.3; p⳱0.001). The study also analyzed the association between symptoms of depression and cognitive status, adjusted for age, gender, and education. Different logisticregression models were created for dementia and

FIGURE 2.

very early dementia. The ORs of dementia and very early dementia in relation to increasing severity of symptoms of depression (5-point increase on the Geriatric Depression Scale) were, respectively, 2.9 (95% CI: 1.9–4.6; Wald v2[1]⳱22.2; p ⬍0.001) and 1.7 (95% CI: 1.2–2.5; Wald v2[1]⳱10.2; p⳱0.001). Separate analyses were conducted for men and women. Results for women were similar to those for the entire population; whereas the association between increasing severity of depressive symptoms, dementia, and very early dementia was not statistically significant for men. It is important to note that in 4 out of 19 subjects with dementia, the assessment of depression was not possible because of the severity of the dementia itself. The remaining subjects with dementia had scores of 11 or more on the GDS. These findings confirm the difficulty of detecting symptoms of depression in people with dementia by use of questionnaires. Thus, we omitted the subsample with dementia in further analyses. The study investigated the combined effect of very early dementia and symptoms of depression on IADL disability, controlling for sociodemographic characteristics (Table 3). In these analyses, the reference group was defined as being cognitively normal and having no depressive symptoms. Veryearly-dementia alone was strongly associated with IADL disability, and this association tripled in sub-

Prevalence Per 100 People of Dependence in IADL Items in Dementia, Very Early Dementia, and Normal Elderly People

Ability to handle finances

Responsibility for own medications

Dementia Very early dementia Normal

Modes of transportation

Shopping

Ability to use telephone

0

20

40

60

80

100

Prevalence (per 100 People)

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Prediction of Functional Disability jects with both very early dementia and depressive symptoms. Increasing age and female gender emerged as independent risk factors for IADL disability. These results could be verified in supplementary analyses, taking into account the very-early-dementia subjects who had a documented cognitive and functional decline during the follow-up period of 3 years (16 of the 23 very-early-dementia subjects). The findings confirmed that the presence of symptoms of depression tripled the risk of disability. Table 4 shows the ORs for different IADL disabilities associated with very early dementia, symptoms of depression, age, and female gender. Among cognitively normal subjects, symptoms of depression did not affect dependence in any IADL item. Having Very Early Dementia and No Symptom of Depression were related to disability in “mode of transportation” and in “ability to handle finances.” Having sympFIGURE 3.

toms of depression and very early dementia was consistently related to disability in all individual IADL items. An increase in age emerged as an independent risk factor for dysfunction in all individual IADL items, whereas being a woman was related to disability in “mode of transportation.” These findings remained unchanged when we repeated the analyses, considering the very-early-dementia subjects who had a documented cognitive and functional decline during the follow-up. Current physical diseases were taken into account as possible confounders. When cardio- and cerebrovascular diseases, fractures and osteoarticular diseases, and malignancy were introduced into the models, the results for the combined effect of symptoms of depression and very early dementia on functional disability remained unchanged. Finally, further analyses showed that the introduction of the stratification

Prevalence Per 100 People of Dependence in IADL Items in Elderly People With and Without Symptoms of Depression

Ability to handle finances

Symptoms of depression No symptoms of depression

Responsibility for own medications

Modes of transportation

Shopping

Ability to use telephone

0

10

20

30

40

Prevalence (per 100 People)

TABLE 3.

Odds Ratios (OR), 95% Confidence Intervals (CI), and p Values for IADL Disability, for Combined Effects of Symptoms of Depression and Very Early Dementia, Adjusted for Age, Gender, and Education IADL Disability

Normal, without symptoms of depression Normal, with symptoms of depression Very early dementia, without symptoms of depression Very early dementia, with symptoms of depression Age (increment of 1 year) Female gender

OR

95% CI

Wald v2[df]

p

1.0 1.5 11.5 37.4 1.3 5.9

0.3–8.0 1.2–114.0 5.2–266.1 1.1–1.6 1.2–28.1

0.3[1] 4.4[1] 13.1[1] 10.8[1] 5.0[1]

0.61 0.04 ⬍0.001 0.001 0.03

Note: IADL: Instrumental Activities of Daily Living.

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0.02

⬍0.001

0.06

0.006

5.5[1]

11.0[1]

3.5[1]

7.6[1]

0.055

0.003

0.06

0.006

3.7[1]

8.5[1]

3.5[1]

7.5[1] 0.002 9.5[1]

0.01 6.0[1]

0.002 9.8[1]

0.04 4.1[1] 0.42

0.03

0.32

⬍0.001

0.7[1]

4.7[1]

1.0[1]

13.5[1]

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Note: Of 195 persons, there were only 2 with disability in “using the telephone;” therefore, it was not possible to calculate the ORs for this IADL item. IADL: Instrumental Activities of Daily Living.

0.70 0.2[1]

1.0 0.6 (0.1–6.9) 19.9 (1.6–241.2) 46.4 (4.8–448.0) 5.6 (0.9–33.7) 1.4 (1.1–1.8) 0.74 0.1[1]

1.0 0.7 (0.1–7.6) 12.4 (0.95–162.2) 48.3 (3.6–649.0) 7.4 (0.9–61.3) 1.7 (1.2–2.4) 0.31 1.0[1]

1.0 2.2 (0.5–10.1) 9.8 (1.1–89.6) 18.8 (3.0–117.9) 7.1 (1.5–34.0) 1.3 (1.1–1.5) 0.75 0.1[1]

OR (95% CI) Wald v2[df] OR (95% CI) Wald v2[df]

p

OR (95% CI) Wald v2[df]

p

OR (95% CI)

Wald v2[df]

p

Ability to Handle Finances IADL Disability

Responsibility for Own Meds Mode of Transportation Shopping

1.0 1.2 (0.4–3.5) Very early dementia, without symptoms of depression 2.2 (0.3–15.5) Very early dementia, with symptoms of depression 4.8 (1.2–19.7) Female gender 1.7 (0.6–4.7) Age (increment of 1 year) 1.2 (1.1–1.3) Normal, without symptoms of depression Normal, with symptoms of depression

TABLE 4.

Odds Ratios (OR), 95% Confidence Intervals (CI), and p Values for IADL Disabilities, for Combined Effects of Symptoms of Depression and Very Early Dementia, Adjusted for Age, Gender, and Education

p

De Ronchi et al. variables as covariates into the models did not influence the findings (data not shown).

DISCUSSION The main findings of this study can be summarized as follows: 1) Late-life symptoms of depression are common in people with very early dementia; 2) In subjects diagnosed with very early dementia, the presence of symptoms of depression tripled the risk of disability; 3) Age and female gender consistently emerged as independent risk factors for functional disability in subjects with very early dementia. Prevalence of Symptoms of Depression in Very Early Dementia Symptoms of depression occur more frequently in elderly persons with dementia,24,43 in persons in the preclinical phase44 or in early stages of AD,45 and also in subjects with mild cognitive impairment46 than in cognitively intact elderly persons. In our least-educated population of very-early-dementia elderly subjects, symptoms of depression were twice as frequent as in normal subjects (70% versus 35%). In previous studies, the presence of a depressive syndrome among subjects with mild cognitive impairment varied from 20%46 to 30%.47 This different rate can be explained by methodological differences in diagnostic criteria and procedures. The reciprocal influence of depression and cognitive impairment has been previously investigated, with conflicting results. Some demonstrated that depression could be a risk factor for the incidence of cognitive decline,13–18 but other cohort studies failed to replicate this finding;19–22 in fact, a recent study suggested that subclinical impairments of attention and memory could precede depressive symptomatology, with a common physiologic pathway possibly underlying both processes.24 However, the causal relationship between depression and cognitive impairment has not yet been unequivocally determined. Symptoms of Depression and Disability in Very Early Dementia Depression affects the functional status of elderly persons3–6,25 and causes an excess of disability in persons with dementia.48,49 However, dementia is only

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Prediction of Functional Disability the end-point of the cognitive continuum scale, in which very early dementia represents an emerging concept, defined as a state characterized by lower cognitive performance than would be expected given the age and educational background of the person50 and by mild deficits in higher-order functional tasks (e.g., IADLs), such as the ability to travel or manage complex activities. Recent studies have suggested that, even in the very early clinical phases of dementia, elderly persons can experience changes in managing daily functions.9,38,39 Considering the complex relationship between cognitive impairment, depressive symptoms, and functional decline, Mehta et al.7 argued that, in elderly subjects with no ADL dependence at baseline, cognitive impairment and depressive symptoms are independent predictors of functional decline. Other studies have examined the relationship between cognition, depression, and disability. However, three of these studies25–27 included subjects with MMSE scores of at least 23 and above, thus taking into account only almost-cognitively-intact elderly subjects. In other studies, the term cognitive impairment was used for the whole range of cognitive disturbances, from cognitive impairment to overt dementia.7 This study was the first in which very early dementia was diagnosed according to the international criteria used in large, population-based studies,11,50 also taking into account mild deficits in higher-level functions, such as the ability to travel or manage complex activities.9 The results of this study clearly suggest that symptoms of depression more than tripled the risk of functional dependence in people with very early dementia. In fact, although very-early-dementia subjects had an 11-fold higher risk than normal persons for IADL disability, people with both very early dementia and symptoms of depression reached a 37fold higher risk for functional dependence. Similar results were obtained taking into account the subsample of very-early-dementia subjects who had a documented cognitive and functional decline during the follow-up period of 3 years. Age, Gender, and Functional Dependence In agreement with most studies,4,50–52 this study demonstrated that older age and female gender50,53,54 emerged as risk factors for functional dependence in elderly persons. The association between increasing

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age, female gender, and IADL disability was independent of all other putative risk factors. The interpretation of these findings needs to take into account several considerations: First, knowledge concerning the type and extent of functional disability in very early dementia is limited, and the lack of clear criteria for the identification of what constitutes relevant functional activities, or impairments in the performance of such activities, is a huge difficulty.9,55,56 Moreover, many factors, including age and low level of education, may contribute independently to disability. Second, although the 30-item version of the Geriatric Depression Scale (GDS) is an accurate screening test for depression in geriatric populations and has been recommended by the British Geriatrics Society,57 it does not maintain its validity in people with dementia,58 and it should not be used as a proxy for diagnosis, especially in patients who may have serious cognitive impairment. Also, the contrasts between the dementia and the other groups are problematic in that the majority of the subjects with dementia and very early dementia have high GDS scores. Therefore, the attribution of the functional impairments can be confounded. Another important concern regarding this study is that IADL is not designed to evaluate the impairments linked to depression. Items that are more important for measuring the outcome of depression are not included in the scale. A third limitation in the present study relates to the use of the MMSE to define cognitive impairment. The use of a global measure of cognitive performance may be questionable; however, the MMSE has been found (in the guidelines for the Report of the Quality Standards Subcommittee of the American Academy of Neurology59 to be a useful tool for assessing degree of cognitive impairment. Also, the overall performance of the MMSE has good concurrent validity with other comprehensive neuropsychological assessment instruments,60 and MMSE scores were found to be reliable predictors of AD.61 Moreover, the MMSE is a quick and simple tool, and the proposed definition of very early dementia can be used in medical care at the primary level to identify high-risk individuals for further assessment in a specialized clinical setting.11 Another possible concern is that the definition of cognitive impairment was based on ageand education-adjusted norms. This method was specifically chosen because age and education affect MMSE performance. Thus, it would be inaccurate to

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De Ronchi et al. define cognitive impairment according to a cut-off based on a global performance mean. Moreover, because the MMSE is less reliable in people with little or no education, this might have led to higher prevalence of the diagnosis of very early dementia in this study. Fourth, there are potential limitations in the preliminary diagnosis because the two physicians who administered the MMSE also were the same who collected clinical information about the person’s functional status (by use of the Global Deterioration Scale and the IADL scale) and clinical status. Fifth, the dropout rate deserves further discussion, given that 17.9% of subjects died before undergoing this examination, and 23.9% of the subjects refused to participate in the study. The deceased subjects more frequently had dementia, were men, and were older than the participants, and the refusals more frequently had dementia and were more educated than those who underwent the clinical examination. This may bias our results toward an underestimation of the prevalence rate of dementia and toward an overestimation of the prevalence rate of dementia and very early dementia among younger subjects, women, and subjects with a lower educational level. Sixth, the findings of this study are based on prevalence figures, which imply that differential survival among subjects with dementia needs to be taken into account. Seventh, the findings are limited by the relatively small sample sizes. Also, we must note that the odds ratios for very early dementia, with and without symptoms of depression, encompasses very wide

confidence intervals, and the confidence intervals substantially overlap. Therefore, we cannot rule out the possibility that our findings may have been affected by low power in detecting significant differences in odds ratios between the two groups. Finally, because the study was carried out among persons with low-to-moderate education, the results might not generalize to groups with higher education levels. Despite these limitations, the results suggest that elderly subjects suffering from very early dementia and who have symptoms of depression are at very high risk of functional disability and have a strong need for accurate diagnostic assessment. If confirmed, our results are relevant for prevention, because these subjects may be a suitable target group for intervention before they develop severe disability.62 Furthermore, because subjects with very early dementia and symptoms of depression represent a large proportion of the elderly population, preventive intervention has the potential for dramatic public health impact. We are indebted to all the members of the Faenza Project, for data collection, Anna Rita Atti, for her help in manuscript revision, and to the Editor and the anonymous reviewers of The American Journal of Geriatric Psychiatry for their thorough and insightful review of the manuscript. The research described in this article was supported in part by grants from the Italian Ministry of University and Scientific Research and Technology (MIUR 60%) awarded to Dr. De Ronchi.

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