Objective: To test the hypothesis that specific psychopathological non-cognitive symptoms are associated with incident mild cognitive impair-ment (MCI), while different symptoms are asso-ciated with incident dementia of Alzheimer's type (DAT). Methods: A representative commu-nity sample of 4,803 individuals aged 55+ years was interviewed in a two-phase screening, in Wave I or ZARADEMP I. This is the baseline, cross-sectional study of the ZARADEMP Project, a longitudinal study to document incidence and risk factors of dementia. The main instrument for assessment of participants was the ZARADEMP Interview, which includes stan-dardized Spanish versions of instruments such as the Mini-Mental Status Examination and the Geriatric Mental State GMS-AGECAT. Two years later, in Wave II or ZARADEMP II, the cognitively non-deteriorated elderly were reas-sessed in a similar, two-phase procedure. "Incident cases" of both dementia and DAT (DSM-IV-TR criteria), as well as MCI (opera-tionally defined Petersen's criteria) were diag-nosed by a panel of psychiatrists. Statistical, logistic regression models, adjusted by age, sex

and education were used to test the hypothesized association. Results: "Irritability", "neurovege-tative symptoms", "sleep problems", "concen-tration difficulties", "loneliness" and "subjec-tive slowing" documented at baseline were asso-ciated with incident MCI (odds ratio, OR range 1.71-2.67). A different profile of non-cognitive symptoms was associated with incident DAT, specifically "tension" (OR= 2.45), "sleep prob-lems" (OR= 2.81), and "observed slowing" (OR= 4.35). On the contrary, "subjective restric-tion of activities" seemed to be negatively associ-ated with DAT (OR= 0.12). Conclusions: To our knowledge, this is the first report about some specific psychopathological, non-cognitive symp-toms associated with incident MCI and/ or inci-dent DAT, when controlling by each other. The psychopathological profile associated with MCI is different from the profile preceding DAT.

Keywords: Dementia; Dementia of Alzheimer's Type; Community study; Non-Cognitive symptoms;Logistic regression model

F.P. Graham Publishing Co.

Non-Cognitive Psychopathological Symptoms Associated with Incident Mild Cognitive Impairment and Dementia, Alzheimer's TypeANTONIO LOBOa,b, RAÚL LÓPEZ-ANTÓNb,c, CONCEPCIÓN DE-LA-CÁMARAb,c, MIGUEL ÁNGEL QUINTANILLAc, ANTONIO CAMPAYOb,c, PEDRO SAZb,d and ZARADEMP WORKGROUP

aDepartment of Psychiatry, University of Zaragoza, Instituto Aragonés de Ciencias de la Salud and Hospital Clínico Universitario, Zaragoza, Spain; bCentro de Investigacion Biomédica en Red de Salud Mental (CIBERSAM), Ministry of Health; cInstituto Aragonés de Ciencias de la Salud and Hospital Clínico Universitario, Zaragoza, Spain; dDepartment of Psychiatry, University of Zaragoza, Spain. alobo@unizar.es

(Submitted 22 October 2007; Revised 18 February 2008; In final form 18 February 2008)

*Corresponding author: Tel.: +34 976 55 11 67; FAX: +34 976 76 17 12; E-mail: alobo@unizar.esISSN 1029 8428 print/ ISSN 1476-3524 online. © 2008 FP Graham Publishing Co., www.NeurotoxicityResearch.com

Neurotoxicity Research, 2008, VOL. 14(2,3). pp. 263-272

A. LOBO et al.264

INTRODUCTION

There is an increasing concern for the problem of dementia in the elderly population. Most current concepts of dementia follow the so called "cogni-tive paradigm" (Berrios, 1989). The essential char-acteristic of dementia in the influential DSM-IV-TR is "the development of multiple cognitive deficits", specifically "impaired memory" and "at least one of the following: aphasia, apraxia, agnosia and distur-bance in executive functioning" (American Psychiatric Association, 2000). While the DSM-IV-TR also describes "associated symptoms" (e.g., lack of insight and unrealistic assessment of his/her own abilities; anxiety and depression; delusions and hallucinations; etc.), they are not included among the diagnostic criteria. However, the limita-tions of the "cognitive paradigm" have been under-lined (Berrios, 1989). This author has pointed out that "the major disintegration of psychological organisation which is characteristic of dementia is likely to involve other systems such as perception, motility, personality organisation, emotional expe-rience and volition". Non-cognitive psychopathological symptoms, which have been called "behavioural and psycho-logical symptoms of dementia" (BPSD) (Finkel et al., 1997), have lately stirred considerable interest: they are common both in clinical samples (Ortiz et al., 2006) and in the general population (Lyketsos et al., 2002); and they are considered to predict a poorer outcome (Chan et al., 2003; Shin et al., 2005). We have recently shown that affective symp-toms, and particularly negative-type symptoms are very frequent in cases of dementia living in the community, the latter having powerful specificity in the distinction with non-cases (Saz et al., 2008). Depression has been associated with subsequent dementia (Jorm et al., 1991), but other studies could not confirm the association with depressive symptoms (Ganguli et al., 2006). Furthermore, there is not much evidence about other non-cogni-tive, psychopathological symptoms preceding the onset of dementia. While non-cognitive symptoms such as the affective ones might be considered sec-ondary manifestations of a dementing illness or a psychopathological reaction to the handicaps in the demented, these symptoms, but particularly nega-tive-type symptoms could also be studied as possi-

ble risk factors and/or early markers or prodromic manifestations of dementia (Teng et al., 2007). On the other hand, mild cognitive impairment (MCI) has emerged in the field of dementia studies, and has been suggested as a transitional stage between age related memory decline and dementia of Alzheimer's type (DAT) (Modrego and Ferrandez, 2004). Conversion rates from MCI to DAT range from 4% to 23% in community based samples (Bruscoli and Lovestone, 2004) and 10% to 31% in clinic-based samples (Luis et al., 2003). This vari-ability may be related to differences in diagnostic criteria, but also to sample selection. On the basis of both clinical experience and preliminary analysis of our previous research, we maintain the general hypothesis that MCI such as it is described in the literature is in fact a heterogeneous group of distur-bances of mild severity, which includes early cases of dementia, but also affective disorders. We are involved in the ZARADEMP Project, a longitudinal study of dementia and psychiatric mor-bidity in a large, representative sample of the elderly population. In this setting, the objective of this paper was, first, to study the association of specific non-cognitive, psychopathological symp-toms assessed during the baseline study with inci-dent cases of dementia and DAT, but also of MCI. And second, to test the hypothesis that the profile of associated symptoms of dementia, and specially DAT, is different from the profile in MCI, affective symptoms being more frequent in the latter.

METHOD

Background, Design and Sampling TechniqueThe ZARADEMP Project is a longitudinal, three-wave epidemiological study designed to document the incidence of dementia, and to complete a case-control study of risk factors in incident cases. The objectives and methods of the project have been described elsewhere (Lobo et al., 2005). The site of the study was Zaragoza, the fifth largest city in Spain (622,371 inhabitants). We report here from the baseline, cross-sectional study or ZARADEMP-I (Z-I), and from the first follow-up wave or ZARADEMP-II (Z-II). A stratified random sample of individuals aged 55+, with proportional alloca-tion by age and sex, drawn from census lists was selected in the baseline. The refusal rate was 20.5%,

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and ultimately 4,803 people were interviewed. After excluding cases and subcases of dementia for the follow-up (n=742), 4,061 individuals were approached for Z-II, and eventually 3,244 indi-viduals were interviewed, the refusal rate being 9.9% (n=402). We report here data from the inci-dent cases identified during the follow-up period in Z-II.

InstrumentsThe ZARADEMP Interview was used in this proj-ect. It incorporates several international instru-ments, previously standardized in Spain by our research group. For the purpose of this report, the following will be described:

Geriatric Mental State (GMS), a semi-structured stan-dardized clinical interview for assessing the mental state of elderly persons (Copeland et al., 1987; 1992). It includes neuropsychological items and a computer-ized diagnostic program, AGECAT, can be applied (Copeland et al., 1987; Saz et al., 1996). For the purpose of this study, GMS symptoms different from those included in the main "cogni-tive" category in DSM-IV-TR are called "non cognitive". We selected 23 of these psychopatho-logical symptoms, which are grouped in three

categories: "affective", "negative-type" and "other symptoms" (FIG. 1). They include the nuclear symptoms for each non-cognitive section of the GMS, and both affective-type symptoms and negative-type symptoms receive special emphasis, because of their special relevance for this study. Following standard procedures, "0" was the score when the symptom was absent. However, scores "1" (symptom present, but mild or not frequent) and "2" (symptom frequent and/or severe) were collapsed for the calculation processes. History and Aetiology Schedule (HAS) (Copeland et al., 1987; Dewey et al., 1992); a standardized method of collecting history data from a caregiver, or directly from the respondent when he is judged to be reliable. It is crucial to complete the GMS and facilitate a diagnostic process using the DSM system. Mini-Mental Status Examination (MMSE; Folstein et al., 1975; Lobo et al, 1999), frequently used internationally to detect cognitive decline. Lawton & Brody Scale (Lawton and Brody, 1969; Tarraga, 1995) and Katz' Index (Katz et al., 1963; Alvarez et al., 1992) were used to assess instrumental and basic activities of daily living, respectively, and to assess disability (total score and number of items).

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ProcedureA two-phase epidemiological screening design was used in the baseline study (Z-I) and a similar meth-od was used in the follow-up wave (Z-II). In Phase I trained senior medical students administered the ZARADEMP Interview to participants at home. Outside caregivers were interviewed when the par-ticipant was considered to be unreliable. Medical reports, which are frequently available at partici-pants' homes, were used in the diagnostic process. Participants were nominated as "probable cases" on the basis of GMS threshold "global" score and/or Mini-Mental standard cut-off points. In Phase II of Z-I the supervising, trained research psychiatrists reassessed, using the same instruments, in the par-ticipant's home, those cases of dementia considered to be doubtful according to predetermined criteria. The data on the remaining participants were thor-oughly reviewed by the psychiatrists supervising individually the lay interviewers. However, in Z-II all probable cases of dementia were reassessed by research psychiatrists. Our previous studies have supported the validity of this diagnostic process done by research psychiatrists in the community (Lobo et al., 1995). Patients diagnosed of dementia by the research psychiatrist, but also the elderly considered to be subcases of cognitive deficit on the basis of scores below the standardized threshold point in GMS and/or MMSE were removed from the follow-up sample. The cohort of the non-demented, non-cognitively deteriorated elderly composes the sample followed up in consecutive phases of the Project, starting by Z-II. In the follow-up wave, or Z-II, the diagnosis of "incident case" of dementia was confirmed, when appropriate, by a panel of research psychiatrists. For the diagnostic process, variables in the ZARADEMP Project Interview were operational-ized to conform with DSM-IV-TR criteria. For the diagnosis of dementia the following DSM-IV-TR criteria were required: A1. Impaired memory in the short and long term. A2. At least one of the follow-ing cognitive disturbances: a) Aphasia b) Apraxia c) Agnosia d) Disturbance in executive functioning. B. The cognitive deficits in criteria A1 and A2 each cause significant impairment in social or occupa-tional functioning and represent a significant decline from a previous level of functioning. C. The deficits do not appear exclusively during the course of a

delirium. D. The disturbance in not better account-ed for by another Axis I disorder (e.g., Major Depressive Episode, Schizophrenia). For the diag-nosis of DAT, DSM-IV-TR criteria were also required: A. All criteria for dementia described in the previous paragraph B. The course is character-ized by gradual onset and continuing cognitive decline. C. The deficits of the criteria A1 and A2 for dementia are not due to: C1 Other central ner-vous system conditions that cause progressive deficits in memory and cognition. C2 Systemic conditions that are known to cause dementia. C3 Substances-induced conditions. For the diagnosis of MCI, we have operationalized Petersen et al.'s, (1999) criteria, using information from the ZARADEMP Interview, as follows. Subjects ful-filling DSM-IV-TR criteria of dementia or scoring below the MMSE standard threshold point were excluded. Inclusion criteria were: an abnormal score in the memory items of both the MMSE and the GMS ("subjective memory loss" and "observed memory loss"); and scores in the normal range on both, Lawton & Brody and Katz's Index of ADL's. We used as a comparison group the non-cases in Z-II, by eliminating from the sample all GMS cases of dementia, as well as other GMS cases, in particular cases of depression and anxiety.

Quality Control and EthicsSystematic checks on the reliability of the assess-ments were implemented to prevent the "reliabili-ty-drift". Standard ethical principles were main-tained throughout the study. Participants were given a standard information sheet, written con-sent was obtained, and privacy, confidentiality and security were maintained, according to Spanish Law 5/1992.

Statistical ProceduresStatistical analyses were performed using SPSS 14.5 for Windows. Z test was used to calculate dif-ferences in frequencies, by groups, with P <0.05 as the level of significance. We calculated Student's t to test differences by sex, age and education for quantitative variables. Confidence intervals (95%) and standard deviations were also calculated. To investigate the association of incident cases of dementia, DAT and MCI with psychopathological symptoms at baseline, stepwise logistic regression

NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT 267

models were used. The 23 identified non-cognitive symptoms were introduced as explanatory vari-ables, keeping sex, age and education as fixed covariables. We chose a stepwise backwards condi-tional selection method, that allows for identifica-tion of variables that significantly contribute to the predictive capacity of the model, optimizing the R2 coefficient. For each variable, the criterion for leav-ing the model was a significance of P >0.005. A small amount of GMS data was missing (< 5%).

RESULTS

Demographic characteristic of both samples are summarized in Table I. In both, women and the elderly with limited educational background pre-dominate. As expected, mean age in Z-II tends to be older, although differences with Z-I were not statistically significant. Mean scores in the Mini-Mental are higher in Z-II, (t=5.99; p < 0.001) but this might also be expected, since cases of demen-tia and cognitively deficient elderly had been removed from the baseline sample for the follow-up assessment in Z-II. Eighty two cases of demen-tia, 47 cases of DAT and 208 cases of MCI were

identified in Z-II, and 1,645 elderly were consid-ered to be non-cases. Table II shows results of step-wise logistic regres-sion analysis to test the association of non-cognitive psychopathological symptoms assessed in the base-line with incident cases of MCI. In the fitted final model, most symptoms assessed in the affective section of the GMS ("irritability", "neurovegetative symptoms", "sleep problems", "loneliness" and "concentration difficulties") remained associated with MCI, although "dysphoric mood" or "anxiety" were not. Similarly, the association with "subjective slowing" was also documented. Table III shows the results in relation to incident cases of dementia. Sleep difficulties documented at baseline were also associated to the incident cases, but not the remaining affective symptoms. "Observed slowing" was very significantly associ-ated to incident dementia (OR = 6.70; 95% C.I. [3.04-14.78]). On the contrary, "subjective restric-tion of activities" seemed to be inversely associated with dementia. "Sleep problems", but also "tension", a relevant affective symptom, documented at baseline was associated with incident cases of DAT (Table IV).

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Again, "observed slowing" was very significantly associated with the outcome of DAT at follow-up (OR = 4.35; 95% C.I. [1.48-12.80]) and "subjec-tive restriction of activities" seemed to be nega-tively associated with dementia (OR = 0.12; 95% C.I. [0.02-0.63]).

DISCUSSION

This is the first study trying to document the asso-ciation of non-cognitive, psychopathological symp-toms assessed at baseline and incident cases of dementia and DAT, but also of MCI simultaneously.

NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT 269

Some previous studies documented the association of depression and dementia (Devanand et al., 1996; Geerlings et al., 2000; Green et al., 2003). However, reports are discrepant, since other studies could not confirm these findings (Dufouil et al., 1996; Vinkers et al., 2004; Ganguli et al., 2006). We have attempt-ed a different approach, since we studied individual affective, but also non-affective symptoms, control-ling by each other rather than disorders. We show that "tension" but also "sleep problems" at baseline are followed by incident DAT, after controlling by other affective and non affective phenomena. Obviously, it might be argued that "sleep problems" are not necessarily affective symptoms. Sleep dif-ficulties have been found to be common in cases of dementia (Vitiello and Borson, 2001; Onen and Onen, 2003), and the possibility exits that they are symptoms directly due to brain disease. However, the relevant finding here, which has not been reported previously, is that the sleep problems pre-cede the onset of the dementing condition. New studies could clarify to what extent these symptoms must be considered risk factors or, on the contrary, early manifestations of the dementing illness. In fact, a similar argument might be put forward in relation to the affective symptoms preceding a diagnosis of dementia at follow-up. A muti-facetted relationship between depression and dementia has been previously discussed (Mahendra, 1985; Lobo et al., 1995). Affective symptoms might be risk fac-tors for dementia (Chen et al., 1999) but also an early manifestation of brain disease (Wilson et al., 2002; Green et al., 2003). Careful psychopatho-logical analysis may be useful in future studies to clarify this dilemma, since symptoms of brain con-ditions may be phenocopies (Bulbena and Berrios, 1993), with qualitative differences from symptoms in primarily psychiatric illness. In relation to this, we believe the use of the GMS, a psychiatric instru-ment is one asset in this study. We have also studied non-cognitive symptoms, mainly negative-type symptoms related to apathy, assessed at baseline. An association of "observed slowing", which is also a psychomotor symptom, with incident DAT is documented here. Previous authors have reported an association of apathy with dementia (Lyketsos et al., 2002). However, we show that it is specifically "observed slowing" the symptom strongly associated with incident global

dementia (OR = 6.70) and specifically incident DAT (OR = 4.35). No association was found with other apathy related symptoms, such as "anhedo-nia" or "anergia", when controlling for the remain-ing affective and non-affective symptoms. From the clinical point of view, it may have special interest to document "observed slowing" in the non-dement-ed elderly, particularly when accompanied by "ten-sion" since both were associated with future DAT. We may also speculate about the theoretical inter-est of these findings, in particular in DAT, since "global dementia" refers, by definition, to a group of disorders with a common syndrome of cognitive deterioration. Present day, psychiatric research is searching for endophenotypes that might be mark-ers for genetic conditions such as DAT. Apathy might be one such an endophenotype (Borroni et al., 2006), but this study suggests that more spe-cific symptoms, such as "observed slowing" might be studied as potential, early markers. The finding that "subjective restriction of activities" has a negative association with dementia and DAT was unexpected. It might be related to the insight healthy elderly people have about deficits in a nor-mal ageing process. In any case, the results in this study suggest that special clinical interest, and even theoretical interest, should be paid to patients with "objective slowing", but not "subjective restriction of activities", since they might be at special risk for DAT. We believe that the results of this study tend to support our conjecture that so called MCI is a het-erogeneous group of psychopathological, minor disorders, and not necessarily an early manifesta-tion of a dementing condition. There is consider-able evidence that the conversion rate of MCI into dementia is quite important (Luis et al., 2003; Bruscoli and Lovestone, 2004; Lopez et al., 2007). However, the specific rate varies between studies. We suspect that cases of MCI in some reports included cases or subcases of affective disorder. In support of this conjecture, first, the profile of symp-toms associated to both incident global dementia and incident DAT is different from the profile of incident MCI; and second, contrary to cases of inci-dent dementia, several affective symptoms are associated with incident MCI. Future studies could test more specifically the association of affective disease, and affective symptoms with MCI.

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Among the strengths of the paper, we should underline the fact that a sample of incident cases of dementia and MCI, coming from a large population sample was studied. Furthermore, we are confident that this study fulfils present day requirements in psychiatric epidemiology (Kaelber and Regier, 1995). First, a representative community sample was investigated including both, institutionalized and non-institutionalized elderly. Secondly, screen-ing and case ascertainment instruments specifically developed for the elderly were used; they are wide-ly accepted in the international literature, and were previously standardized in our specific culture. The sensitivity coefficients of the instruments used [GMS "0rganic" = 93.2%; Mini-Mental = 89.8% (Lobo et al., 1995)] are considered adequate and comparable to coefficients reported in several stud-ies in this field (Hofman et al., 1991). Thirdly, although "probable non-cases" among the elderly were not re-assessed in this study, the high negative predictive value of the screening instruments used (Mini-Mental = 97.8%; GMS "organic"= 98.3%) (Lobo et al., 1995) prevents the likelihood of a sub-stantial reduction in the number of dementia cases identified. Finally, the standardized, DSM-IV-TR diagnostic criteria used are considered to be aging appropriate criteria (Jeste et al., 2005). Other limitations of the study should be addressed. The categorization of "non-cognitive" symptoms such as, "lack of concentration" or "difficulties in thinking" in this study may be debatable. However, first, both are subjective symptoms in the GMS glossary; second, they are considered to be part of depressive episodes in the DSM-IV-TR system; and third, they are not included among the cognitive symptoms of dementia in this diagnostic system. Similarly, neither "subjective restriction of activi-ties" (psychomotor section in the GMS), nor "dis-turbances of perception" (psychotic phenomena section in the GMS) are included among the cogni-tive symptoms in the DSM-IV-TR. While our pre-vious studies have supported the validity of the diagnosis of dementia performed by research psy-chiatrists in the elderly community (Saz et al., 1996), we anticipated some difficulties, particularly in the cases not directly assessed by the psychia-trists. Therefore, we have followed previously determined requirements for the diagnostic process. Firstly, case definitions and standardized levels of

illness were used (Copeland et al., 1987), and were applied consistently to minimize the impact on rates of dementia (Riedel-Heller et al., 2001). Secondly, we operationalized each one of the items in the DSM-IV-TR manual with information com-ing from the standardized assessment instruments used, to minimize the risk of applying diagnostic criteria of dementia differently from other research-ers (Hofman et al., 1991). Thirdly, all the available data were thoroughly reviewed by the psychiatrists supervising individually the lay interviewers before recording a diagnosis of "dementia". Fourthly, the doubtful cases were re-examined by the research psychiatrists. Finally, a panel of research psychia-trists reviewed all cases before making a definitive diagnosis. Furthermore, we have pilot studied again in this project the diagnostic agreement between the psychiatrists supervising the lay interviewers and/or doing the clinical interview in the elderly homes and the panel of psychiatrists reviewing the data: the agreement is considered to be reasonable, as it occurred in 91.4% of individual "cases" and "sub-cases" presented. Important uncertainties in epide-miological studies relate to sample attrition, but a special effort was made to minimize the risk of non-response (Lobo et al., 1995; 2005), and the refusal rate in both waves of the study was comparable to a number of previous reports (Copeland et al., 1987; 1998). In conclusion, this study suggests for the first time that some specific, non-cognitive psychopathologi-cal symptoms assessed at baseline are associated at follow up with incident MCI and/or incident DAT, when controlling by each other. On the contrary, "subjective restriction of activities" was negatively associated with incident DAT. Furthermore, we have found support for the hypothesis that the psy-chopathological profile associated with incident MCI is different from the profile preceding DAT.

Acknowledgements

Supported by Grants from Fondo de Investigación Sanitaria, and the Spanish Ministry of Health, Instituto de Salud Carlos III (grants #94/1562, 97/1321E, 98/0103, 01/0255, 03/0815, 06/0617, G03/128, Red de Enfermedades Mentales, REM-TAP Network #RD06/0011/0010), Madrid, Spain; Spanish Ministry of Health, Instituto de Salud Carlos

NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT 271

III, CIBERSAM #CB07/09/0016, Madrid, Spain. The authors acknowledge the contribution of medical students and the following researchers, who participated in the study: G. Marcos, T. Ventura, J.L. Día, M. Zapata, B. Quetglas, A. Martín, J.A. Montañés, S. Aznar and A. Lobo-Escolar.

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