Late-Life Depression, Mild Cognitive Impairment, and Dementia: Possible Continuum?

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Late-Life Depression, Mild Cognitive Impairment, and Dementia: Possible Continuum? Francesco Panza, M.D., Ph.D., Vincenza Frisardi, M.D., Cristiano Capurso, M.D., Ph.D., Alessia D’Introno, Ph.D., Anna M. Colacicco, Ph.D., Bruno P. Imbimbo, Ph.D., Andrea Santamato, M.D., Gianluigi Vendemiale, M.D., Davide Seripa, Ph.D., Alberto Pilotto, M.D., Antonio Capurso, M.D., Vincenzo Solfrizzi, M.D., Ph.D.

Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%– 83%) than in population-based studies (median: 15.7%, range: 3%– 63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying

Received September 3, 2008; revised May 13, 2009; accepted May 21, 2009. From the Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari (FP, VF, AD’I, AMC, AC, VS); Department of Geriatrics, University of Foggia, Foggia (CC, GV); Research and Development Department, Chiesi Farmaceutici, Parma (BPI); Department of Physical Medicine and Rehabilitation, University of Foggia, Foggia (AS); and Department of Medical Sciences, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia (DS, AP), Italy. Send correspondence and reprint requests to Francesco Panza, M.D., Ph.D., Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Policlinico, Piazza Giulio Cesare, Bari 11-70124, Italy. e-mail: [email protected] © 2010 American Association for Geriatric Psychiatry

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Panza et al. neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum. (Am J Geriatr Psychiatry 2010; 18:98 –116) Key Words: Dementia, depression, epidemiology, mild cognitive impairment, predementia syndromes

T

he transitional phase between mild nondisabling cognitive decline and disabling dementia is an ambiguous diagnostic period during which it is unclear whether mild cognitive deficits predict incipient dementia or not. In this article, we will use the term “predementia syndrome” to identify all conditions with age-related deficits in cognitive function reported in the literature, including a mild stage of cognitive impairment based on normal or pathological conditions considered predictive or early stages of dementia.1,2 Such predementia syndromes have been defined for Alzheimer disease (AD) but have not yet been operationalized for vascular dementia (VaD) and other specific forms of dementia. However, not all these conditions are progressive (e.g., dementing), but they may be stable or also reversible.1,2 Neuropsychiatric symptoms may accompany these predementia syndromes and help in identifying incipient dementia. In particular, in older adults, depression may be associated with an increased risk for dementia. It may be of crucial interest to determine what presentations of predementia syndromes and depression are progressive/ dementing and which are not. First aim of this review article was to summarize the findings of the studies of depressive symptoms or depression in patients with mild cognitive impairment (MCI) and other predementia syndromes. Furthermore, we attempted to clarify the relationships among late-life depression, MCI, and dementia, reviewing studies that examined the possible impact of depressive symptoms on incident MCI or its progression to dementia, as well as the possible mechanisms behind the observed associations. We reviewed clinical and epidemiologic studies from the English literature published before September 2008, including studies that provided a description of the MCI or depression diagnostic criteria used or describing the means of collecting depressive symptoms. We

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searched through the PubMed database of National Center for Biotechnology Information (available at: http://www.ncbi.nlm.nih.gov) by author and the following keywords: mild cognitive impairment, depression, depressive symptoms, predementia syndromes, prodromal Alzheimer disease, and MCI. Using the PubMed search engine, we found 37 peerreviewed works that satisfied our inclusion criteria. The relevance of the aims of this review was underlined in a recent article, the proceedings of the 2003 National Institute of Mental Health (NIMH) conference “Perspectives on Depression, Mild Cognitive Impairment, and Cognitive Decline.”3 The principal objectives of the meeting were to examine how we might better integrate the varied perspectives on associations among depression, MCI, and cognitive decline and to illuminate the common or distinct mechanisms involved in these associations.3

Predementia Syndromes and MCI Many different diagnostic criteria and terms have been proposed over the years to describe predementia syndromes in the elderly: age-associated memory impairment, aging-associated cognitive decline, cognitive impairment no dementia, and many others.1,2 Furthermore, numerous rating scales for staging dementia include a specific preclinical phase of dementia, e.g., “questionable dementia” in Clinical Dementia Rating Scale (0.5).4 At present, MCI is a clinical label that includes nondemented aged persons with memory impairment and no significant disability.5– 8 The criteria for MCI, as defined by Petersen et al. in 1997, include: 1) memory complaint, 2) objective memory disorder, 3) absence of other cognitive disorders or repercussions on daily life, 4) normal general cognitive function, and 5) absence of dementia.8 In 1997, the emphasis was placed on the compulsory

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Depression and Predementia Syndromes presence of memory complaint and memory disorder.8 In 1999, these criteria were clarified, with MCI defined solely in clinical terms.5 The absence of impaired cognitive function in a domain other than memory is also required. The more recently proposed multiple subtypes of MCI were intended to reflect the heterogeneity of different types of dementia. Actually, there are at least three different subclassifications of MCI according to its cognitive features,8 clinical presentation,7 and probable etiology.1 There is now ample evidence that MCI is often a pathologybased condition with a high rate of progression to AD.1,2 MCI definitions can be broadly classified as amnestic (aMCI) and nonamnestic (naMCI). Therefore, aMCI, with a central role for memory disorder and with relative preservation of other cognitive domains, was identified as the predementia syndrome for AD. aMCI can be subdivided into a single domain subtype with a pronounced memory deficit or a multiple-domain subtype that includes memory impairment along with some impairment in other cognitive domains such as language, executive function, and visuospatial skills.8 The other major MCI subtype is naMCI, which similarly can be subdivided into single and multiple-domain subtypes.8 Moreover, MCI can be further classified in different subtypes according to its cognitive features (dysexecutive MCI and aMCI8) or clinical presentations (MCI with parkinsonism, cerebrovascular disease [CVD], depressive symptoms, or behavioral and psychological symptoms).7 Different MCI subtypes can be defined by probable etiology: MCI-AD, vascular MCI, or MCI-Lewy body dementia.1 A critical review recently took place in Stockholm, then in Montreal to define a new consensus on MCI.7,9 Modification of Petersen’s criteria5,8 was proposed during the conference in Montreal, which was to not require the subjective memory impairment criterion and intact instrumental activities of daily living (Table 1). The European Consortium on Alzheimer’s Disease working group on MCI has very recently proposed a novel diagnostic procedure with different stages, combining neuropsychological evaluation and family interview to detect MCI at the earliest possible stage10 (Table 1). Late-Life Depression In adults older than 65 years, late-life depression refers to depressive syndromes defined in the Diag-

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TABLE 1.

Proposed General Criteria for Mild Cognitive Impairment (MCI) According to the International Working Group on MCI7 and to the MCI Working Group of the European Consortium on Alzheimer Disease10

International Working Group on MCI Criteria 1. Not normal, not demented; does not meet criteria (DSM-IV, ICD 10) for a dementia syndrome 2. Cognitive decline

3. Self and/or informant report and impairment on objective cognitive tasks and/or evidence of decline over time on objective cognitive tasks 4. Preserved basic activities of daily living/minimal impairment in complex instrumental functions

European Consortium on Alzheimer’s Disease MCI Working Group Criteria 1. Cognitive complaint emanating from the patient and/or his/her family 2. The subject and/or informant report a decline in cognitive functioning relative to previous abilities during the past year 3. Cognitive disorders evidenced by clinical evaluation: impairment in memory and/or another cognitive domain

4. Cognitive impairment does not have major repercussions on daily life. However, the subject may report difficulties concerning complex day-today activities 5. No dementia

Notes: Modified from J Intern Med7 and J Neurol Neurosurg.10 DSM-IV: Diagnostic and Stastical Manual of Mental Disorders, 4th Edition; ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th Revision.

nostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV11) and in the International Classification of Disease-10 (ICD-1012) as a mood disorder with symptoms of sadness, negative self-regard, loss of interest in life, and disruptions of sleep, appetite, thinking, and energy level for more than 2 weeks that interfere with daily living. Late-life depression encompasses both late-onset cases and earlyonset cases that recur or continue into later years of life. Various studies present an age range from 45 to 65 years as the lower limit for defining late age of depression onset.13 Late-life depressive syndromes often arise in the context of medical and neurologic disorders.14 The prevalence of major depressive disorder (MDD) is about 17% in patients with AD15 and is even higher in those with subcortical dementias.16 The U.S. NIMH has developed provisional criteria for the diagnosis of depression in individuals with AD to identify the problem and to promote research into the disorder17 (Table 2). Several studies suggesting depression

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Panza et al.

TABLE 2.

Provisional Diagnostic Criteria for Depression of Alzheimer Disease17

A. Three (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: at least one of the symptoms is either 1) depressed mood or 2) decreased positive affect or pleasure 1. Clinically significant depressed mood (e.g., depressed, sad, hopeless, discouraged, and tearful) 2. Decreased positive affect or pleasure in response to social contacts and usual activities 3. Social isolation or withdrawal 4. Disruption in appetite 5. Disruption in sleep 6. Psychomotor changes (e.g., agitation or retardation) 7. Irritability 8. Fatigue or loss of energy 9. Feelings of worthlessness, hopelessness, or excessive or inappropriate guilt 10. Recurrent thoughts of death, suicidal ideation, plan, or attempt B. All criteria are met for dementia of the Alzheimer type (DSMIV-TR) C. The symptoms cause clinically significant distress or disruption in functioning D. The symptoms do not occur exclusively during the course of a delirium E. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse or a medication) F. The symptoms are not better accounted for by other conditions such as major depressive disorder, bipolar disorder, bereavement, schizophrenia, schizoaffective disorder, psychosis of Alzheimer disease, anxiety disorders, or substance-related disorder Specify if Cooccurring onset: if onset antedates or cooccurs with the AD symptoms Post-AD onset: if onset occurs after AD symptoms Specify With psychosis of Alzheimer disease With other significant behavioral signs or symptoms With history of mood disorder Notes: Modified from Am J Geriatr Psychiatry.17 DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision.

as a risk factor for dementia are based on early-onset recurrent or chronic depression rather than on depression occurring for the first time shortly before the dementia is manifested.18 In fact, research suggests that early-onset depression that is untreated or recurrent is associated with volume loss in the hippocampus13 and possibly contributes to dysfunction of the hypothalamic-pituitary-adrenal-stress axis.19 On the other hand, in general, individuals who present with first onset of depression in late life have the higher relative risk of developing some form of dementia.14 There is a general consensus on a syndromal approach to depression, calling on DSM-IV,11 to iden-

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tify symptom clusters such as MDD. In MDD, the use of structured clinical interviewing as the Structured Clinical Interview for DSM-IV allows data acquisition from many sources about past and current psychiatric symptoms and about past and current Axis I diagnoses.20 However, in the elderly, other depression subtypes may be important to the relationship with functional disability and cognitive impairment as MDD, including subsyndromal depression in which symptoms are present intermittently21 and nondysphoric depression in which feelings of sadness are denied.22 In this article, depression will refer to clinically significant depressive symptoms and subsumes MDD, dysthymia, and subsyndromal and other subtypes of depression.3 Furthermore, in many studies of cooccurrence of cognitive impairment and depression, the use of lengthy structured interviews such as the Structured Clinical Interview for DSM-IV is impractical, and researchers often struggle to identify briefer instruments that aid in diagnosis and can track severity of symptoms.3 There are several instruments that are useful for identifying symptoms consistent with depression.13 The Geriatric Depression Scale (GDS) was developed and validated specifically for use with older adults, avoiding somatic and sexual symptoms, evaluating subjective experience of cognitive impairment, and using a simple yes or no response format that decreases cognitive burden.23 There are 15- and 30-item versions of the GDS (GDS-15 and GDS-30), with sensitivities of 80%– 100%.13 A very recent study demonstrated that the GDS-30 is a reliable screening tool for depressive symptoms in MCI but not in patients with AD.24 Another widely used instrument is the Center for Epidemiological Studies Depression Scale (CES-D) composed of 20 items in a multiple-choice format.25 It also developed a 10-item modified version with a dichotomous response scale to avoid confusion among depressed elderly subjects with the multiplechoice format, with comparable sensitivity and specificity to the full version.26 The Beck Depression Inventory is a widely used self-report questionnaire, not developed specifically for older adults but potentially useful, because item content was developed to conform to DSM-IV diagnostic criteria for depression.27 The approach to screening for depression in cognitively impaired individuals also depends in part on the level of cognitive impairment, and for most subjects with even MCI, information from a

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Depression and Predementia Syndromes reliable informant is necessary to assess depression. The Cornell Scale for Depression in Dementia was designed for use in dementia and specifically includes caregivers in the evaluation.28 The Neuropsychiatric Inventory (NPI) is an informant-based interview that assesses neuropsychiatric disturbances commonly seen in patients with dementia.29 Other clinician-based instruments that have been used in studies on MCI and other predementia syndromes include the Hamilton Depression Rating Scale (HDRS),30 the Montgomery-Asberg Depression Rating Scale (MADRS),31 the Comprehensive Psychopathological Rating Scale,32 the Goldberg Depression Scale,33 and the Consortium to Establish a Registry for Alzheimer’s Disease Behavioral Rating Scale for Dementia.34 These instruments are suitable for use with cognitively impaired individuals, but these require training to achieve acceptable reliability for administration and scoring.13 PREVALENCE AND INCIDENCE OF DEPRESSION IN PREDEMENTIA SYNDROMES Prevalence of Depression in Patients With MCI Depression has often been excluded from the definition of MCI, creating a bias in studies on the relationship of depression with predementia syndromes. However, research now indicates a high rate of cooccurrence between depression and MCI that seems to raise the risk for persistent cognitive impairment and dementia.13 Among population-based studies, in the Italian Longitudinal Study on Aging (ILSA), the diagnosis of MCI was associated with a high prevalence of depressive symptoms, with a higher prevalence of mild depressive symptoms (GDS-30: between 10 and 19 points). A prevalence rate of 63.3% of depressive symptoms among patients with MCI was found: 49.3% had mild and 14.0% had severe depressive symptoms (GDS-30 ⬎20 points).35 Findings have been inconsistent mainly because of different procedures in both assessment of depression and MCI definition. In fact, the Cardiovascular Health Study (CHS) Cognition Study was nested within the original CHS cohort, and a subset of demented patients and patients with MCI were assessed with the NPI (Table 3). The CHS Cognition Study reported a cumulative prevalence of 26% for depression among individuals with MCI

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(amnestic or multiple-domain subtypes) relative to 32% in demented subjects.36 Accepting some differences in methodology, the prevalence rates of depressive symptoms assessed with the GDS-30 among patients with MCI in the ILSA were more than twice that found in the CHS Cognition Study. In another study, those classified as MCI had an even lower prevalence of depressive symptoms: only 15.7% as a NPI symptom in the past month.37 In the Kungsholmen project, a Swedish population-based study, the reported prevalence of depression (according to DSM–III–R criteria) in MCI was 10%: 20% reported loss of initiative, 9% loss of interest, 9% suicidal thoughts, 4% depressive thoughts, and 11% reported sadness, as rated using the Comprehensive Psychopathological Rating Scale 38 (Table 3). More recently, two Australian population-based studies assessed depressive symptoms in patients with MCI.39,40 The Goldberg Depression Scale demonstrated limited sensitivity for detection of depressive symptoms in both the patients with MCI (3%) and a healthy control group (2%).39 Using DSM-IV criteria resulted in superior sensitivity in diagnosing minor depression in patients with MCI (17.2%) and control group (3.5%)40 (Table 3). In a Thai population-based study, patients with MCI had higher incidence of anxiety (53%) and dysphoria (46%) measured with the NPI, when compared with normal subjects. Although marginally significant, apathy (12%) was also more common in patients with MCI41 (Table 3). Among hospital-based studies, in a sample of volunteers who responded to advertisements for subjects, nondemented subjects (Clinical Dementia Rating ⫽ 0.5) who progressed to AD had more depressive symptoms and symptoms of personality changes (such as agitation and passivity) at baseline than those who did not progress to AD42 (Table 3). Hwang et al.,43 utilizing the NPI for behavioral assessment, found that the most significant differences between MCI and controls were mood symptoms, including dysphoria, anxiety, and irritability. The larger study by Geda et al.44 reported the substantially lower rate of 9% for depressive symptoms in MCI with the NPI, which was not statistically different from the rate in normal controls. These inconsistent results were derived from methodological differences, with different MCI diagnostic criteria used in these two case– control studies43,44 (Table 3) and with the exclusion of subjects who have concomitant untreated depres-

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TABLE 3.

Principal Prevalence Studies of Depressive Symptoms or Syndromes in Patients With Mild Cognitive Impairment (MCI)

Reference Population-based studies Lyketsos et al.36

Setting and Study Design

Cross-sectional, population based

Subjects

From a total of 3,608 participants, 824 individuals completed the behavioral assessment. Of these, 362 were demented, 320 were MCI, and 142 did not meet criteria for MCI or dementia A total of 454 subjects (dementia, n ⫽ 333; MCI, n ⫽ 121) and their knowledgeable informants

Chan et al.37

Cross-sectional, population based

Forsell et al.38

Cross-sectional, population based

In a population of 443 nondemented persons aged 75 years and older, 89 fulfilled the criteria of MCI and had sufficient data from the psychiatric examination

Kumar et al.39,40

Cross-sectional, population based

2,551 community-dwelling individuals in the age range of 60–64 years

Solfrizzi et al.35

Cross-sectional and longitudinal, population based (3.5 years)

2,963 subjects from populationregister (including institutions) aged from 65 to 84 years

Muangpaisan et al.41

Cross-sectional, population based

107 community-dwelling individuals aged 50 years and older diagnosed with MCI (N ⫽ 77) and normal (N ⫽ 30)

Cross-sectional and longitudinal, case–control, hospital based (3.5 years)

294 subjects at baseline: 19 patients with MCI followed up for a mean of 3.5 years

Cross-sectional and longitudinal, convenience sample recruited through advertisements (3 years)

A total of 165 elderly individuals, from 1,095 who were screened

Hospital-based studies and clinical trials Li et al.55

Copeland et al.42

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Tools, Procedure, or Diagnostic Criteria

Reported Prevalence of Depressive Symptoms or Depression

MCI criteria: ⱖ1.5 SD below age- and education-adjusted norms on standard neuropsychological tests, and depressive symptoms measured with the NPI

26%

MCI criteria: ⱖ1.5 SD on one test or ⱖ1 SD on two or more tests below age- and education-adjusted norms on standard neuropsychological tests and depressive symptoms measured with the NPI and BSRS MCI criteria: 1 SD below age- and education-adjusted norms on MMSE score; depressive symptoms measured with CPRS and diagnoses of depression, anxiety and psychosis were made according to DSM-III-R MCI criteria: SMC, objective memory impairment (score 2 or below on delayed CVLT), normal general cognitive function (MMSE 26 or above), intact ADL; depressive symptoms measured with the GoDS, depressive syndromes diagnosed with DSM-IV MCI criteria: 1.5 SDs below mean age- and education-adjusted on the MMSE and 10th percentile below age- and education-adjusted on memory test, without SMC and intact ADL/IADL); depressive symptoms measured with the GDS-30 MCI criteria: clinical diagnosis according to Petersen’s criteria; depressive symptoms measured with the NPI

15.7%

MCI criteria: cognitive capacity screening examination or MMSE scores between 24 and 26; depressive symptoms measured with the HDRS MCI criteria: CDR ⫽ 0.5; depressive symptoms measured with a semistructured interview with nine questions based on the DSM III-R criteria

Depression: 11%; depressive symptoms: 4%

Depressive symptoms: 3%; minor depression: 17.2%

63.3%

46%

29%

Questionable dementia (stable CDR ⫽ 0.5): 43.5% of depressive symptoms at baseline converters (progressed to probable AD): 45.5% of depressive symptoms at baseline (Continued)

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Depression and Predementia Syndromes

TABLE 3.

(Continued)

Reference

Setting and Study Design

Subjects

Hwang et al.3

Cross-sectional, hospital based

Feldman et al.49

Cross-sectional, clinical trial

Geda et al.44

Cross-sectional, hospital based

Data collected on 514 normal controls, 54 patients with MCI, and 87 patients with mild AD

Gabryelewicz et al.46

Longitudinal, hospital based (3 years)

102 patients with MCI

Lopez et al.45

Cross-sectional, hospital based

A total of 655 subjects, of these 228 were patients with MCI and 427 were probable mild AD

Rozzini et al.47

Cross-sectional, hospital based

A total of 120 subjects were analyzed: 94 of these were classified as aMCI, and 26 as naMCI

Ellison et al.48

Cross-sectional, hospital based

A total of 116 screened patients, of these 59 were patients with MCI (only 38 had also NPI data). Twenty-two of these 38 patients with MCI met criteria for aMCI, whereas 16 met criteria for naMCI

Three age and education comparable groups, i.e., 28 patients with MCI, 124 patients with mild AD, and 50 normal subjects 1,010 patients with MCI

Tools, Procedure, or Diagnostic Criteria MCI criteria: ⱖ1.5 SD below age- and education-adjusted norms on standard neuropsychological tests; depressive symptoms measured with the NPI MCI criteria: CDR ⫽ 0.5 and impaired performance on NYU delayed paragraph recall; depressive symptoms measured with the NPI MCI criteria: clinical diagnosis according to Petersen’s criteria; depressive symptoms measured with the NPI MCI criteria: clinical diagnosis according to Petersen’s criteria and CDR ⫽ 0.5; depressive symptoms measured with the MADRS, depressive syndromes diagnosed with DSM-IV MCI criteria: ⱖ1.5 SD below age- and education-adjusted norms on standard neuropsychological tests; depressive symptoms measured with the CERAD BRSD MCI criteria: cognitive complaint, no dementia, intact general functioning, objective impairment in at least 1 of 4 cognitive domains (cutoff of 1.5 SD with normative corrections for age, years of education, and sex). aMCI criteria: memory impairment either alone or with other cognitive impairments (multiple domains with amnesia); naMCI criteria: single nonmemory domain impaired alone or with other nonmemory deficits (multiple domains without amnesia); depressive symptoms measured with the NPI MCI criteria: clinical diagnosis according to Petersen’s criteria. A diagnosis of aMCI required low performance on the CVLT or a six-item word list recall task, whereas patients with naMCI scored within the normal range on the memory test but at least 1.5 SD below appropriate norms on any of a series of nonmemory cognitive tests; depressive symptoms measured with NPI

Reported Prevalence of Depressive Symptoms or Depression 39%

45%

9%

minor depression: 27%; major depression: 20%

53%

MCI: 68.8%; aMCI: 83%; naMCI: 73.1%

MCI: 63.3%; aMCI: 59.1%; naMCI: 68.8%

Notes: BSRS: Behavior Symptom Rating Scale; MMSE: Mini-mental State Examination; CPRS: Comprehensive Psychopathological Rating Scale; SMC: subjective memory complaint; CVLT: California Verbal Learning Test; ADL: activities of daily living; GoDS: Goldberg Depression Scale; IADL: instrumental activities of daily living; CDR: Clinical Dementia rating Scale; NYU: New York University; CERAD BRSD: Consortium to Establish a Registry for Alzheimer’s Disease Behavioral Rating Scale for Dementia.

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Panza et al. sion in one of the studies.43 Another case– control study reported a prevalence of 53% of depressive symptoms among patients with MCI,45 using the Consortium to Establish a Registry for Alzheimer’s Disease Behavioral Rating Scale for Dementia and MCI criteria identical to those used by Hwang et al.43 (Table 3). The most common depressive symptoms were hopelessness and crying spells, with crying spells more commonly identified in patients with aMCI.45 In their MCI cohort, Gabryelewicz et al.46 showed that as almost half of all patients met DSM-IV criteria for depression: 27% suffered from minor and 20% from MDD (Table 3). The most common symptoms were sadness, poor concentration, inner tension, pessimistic thoughts, lassitude, and reduced sleep. Furthermore, two very recent studies investigated the prevalence in MCI subtypes of neuropsychiatric symptoms and particularly depression47,48 (Table 3). In fact, in another hospital-based study, about 85% of patients with aMCI had some neuropsychiatric symptoms evaluated with the NPI, and the most prevalent symptom was depression, followed by anxiety. A significantly higher prevalence of hallucinations and sleep disorders has been observed in the naMCI group in comparison with the aMCI group.47 Moreover, using NPI, depression/dysphoria (63.3%), apathy (60.5%), anxiety (47.4%), irritability (44.7%), and nighttime behaviors (42.1%) were the most frequent neuropsychiatric symptoms. Although depression/ dysphoria was distributed similarly between aMCI and naMCI, apathy was significantly more frequently associated with aMCI, and nighttime behaviors were more frequently associated with naMCI.48 In these two studies, there were no significant differences in depression rates between patients with aMCI and naMCI.47,48 In a international multicenter, long-term, randomized, placebo-controlled clinical trial, the Investigation in the Delay to Diagnosis of AD with Exelon trial, about 60% of patients with aMCI reported some neuropsychiatric symptoms assessed with the NPI and almost half of the group had reported depressive symptoms (⬎45%)49 (Table 3). Prevalence of MCI in Depressed Patients All the studies cited earlier examined the prevalence of depression or depressive symptoms in patients with MCI; conversely, some studies determined the prevalence of MCI in older patients with

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depression. In fact, elderly patients may have symptoms of both depression and mild cognitive deficits,50 whereas other studies have identified persistent cognitive impairment in depression.51–53 It is important to note that in some of these studies, MCI diagnosis was based on neuropsychological algorithms and not on a traditional clinical definition of MCI.50,51,53 In particular, Reischies and Neu50 found a diffuse mild cognitive disorder in 102 consecutive, depressed elderly patients and 18%–35% of impaired neuropsychological tests in 57 patients with MDD. No improvement in cognitive performance was found at the time of remission of depressive symptoms up to the level of control subjects, suggesting that these patients may suffer from comorbidity of both depression and mild cognitive disorder.50 Butters et al. found that among 45 elderly patients who met DSM-IV criteria for MDD, who had no cognitive impairment at study entry, and who were remitted after a 12-week treatment with nortriptyline or paroxetine had no change in cognitive function as a result of treatment (N ⫽ 35; 77%); in contrast, successful depression treatment led to significantly improved cognitive functioning among elderly depressed patients with baseline cognitive impairment (N ⫽ 10; 23%).51 Adler et al. enrolled 34 depressed elderly of whom 53% with MCI were all treated for depression. At a 6-month followup, the HDRS scores improved in the entire group, whereas cognitive performance remained unchanged and 44% of patients still fulfilled the MCI criteria.52 In another study, 61 depressed patients aged more than 60 years who met DSM-IV criteria for MDD and 40 healthy subjects underwent structural MRI, neuropsychological testing, apolipoprotein E (APOE) genotyping, and salivary cortisol assessment (more than 3 days) with follow-up 6 months later. Persisting MCI according to Petersen’s criteria5,8 was diagnosed in 20 of 49 subjects (41%) at 6 months and was associated with reduced hippocampal volume but not severity of depression, cortisol levels, or APOE genotype.54 In a recent study, Lee et al. enrolled 142 elderly patients with MDD by DSM-IV criteria, instituted antidepressant therapy, and reassessed them a year later. Fifty-five percent of depressed patients who remitted at 1-year follow-up were classified as having MCI at baseline assessment, whereas 44.8% had MCI after 1 year. Of the participants classified as MCI at baseline, 59.4% remained cognitively impaired at 1-year follow-up.

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Depression and Predementia Syndromes By contrast, of the subjects not meeting MCI criteria at baseline, only 26.7% were classified as MCI after 1 year.53 Incidence of Depression in Patients With MCI Very limited evidence is available on the incidence of depression or depressive symptoms in patients with MCI in population-based or hospital-based studies35,55 (Table 4). In the ILSA cohort, an estimated incidence rate of depressive symptoms of 29.6/100 person-years was found, with 8.2/100 person-years of mild new-onset depressive symptoms and 21.4/100 person-years of severe new-onset depressive symptoms.35 A prior nonpopulation-based study of elderly volunteers estimated the incidence of depressive symptoms in patients with MCI to be 11.7/100 person-years,55 which is less than half of the ILSA incidence rate of depressive symptoms of 29.6/ 100 person-years. This underscores the importance of the distinction between population-based and hospital-based settings. The differences between these two incidence studies may arise from selected groups and the different assessment of depression (GDS-30 versus HDRS). The findings from the ILSA suggested a borderline nonsignificant trend for a protective effect against the new-onset of total depressive symptoms in subjects with MCI who reverted to

TABLE 4.

DEPRESSION AND RISK PREDEMENTIA SYNDROMES Converging evidence suggests that late-onset depressive symptoms or syndromes often are a pro-

Principal Incidence Studies of Depressive Symptoms in Patients With Mild Cognitive Impairment (MCI)

Reference Population-based studies Solfrizzi et al.35

Hospital-based studies Li et al.55

normal cognition in comparison with cognitively stable patients with MCI.35 In conclusion, although hospital-based studies on MCI reported a higher prevalence of depressive symptoms (median value: 44.3%), population-based studies reported a prevalence of 3%– 63.3% (median value: 15.7%) for depression among patients with MCI. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. Furthermore, it seems that another important source of discrepancy in prevalence rates of depression in MCI are due more to the operational definition and assessment of depression than the definition of MCI (Table 3). This was also confirmed by the limited evidence coming from studies reporting the incidence of depressive symptoms among patients with prevalent MCI35,55 (Table 4). In particular, use of the NPI seemed to produce higher prevalence of depression, except for the study of Geda et al.44 where the most pure and restrictive definition of MCI according to the Petersen’s criteria was used5,8 (Table 3).

Tools, Procedure, or Diagnostic Criteria

Reported Incidence of Depressive Symptoms or Depression

Setting and Study Design

Subjects

Cross-sectional and longitudinal, population based (3.5 years)

2,963 subjects from populationregister (including institutions) aged from 65 to 84 years

MCI criteria: 1.5 SDs below mean age- and educationadjusted on the MMSE and 10th percentile below ageand education-adjusted on memory test, without SMC and intact ADL/IADL); depressive symptoms measured with the GDS-30

29.6/100 person-years

Cross-sectional and longitudinal, hospital based (3.5 years)

294 subjects at baseline: 19 patients with MCI followed up for a mean of 3.5 years

MCI criteria: cognitive capacity screening examination or MMSE scores between 24 and 26; depressive symptoms measured with the HDRS

11.7/100 person-years

Notes: SMC: subjective memory complaint; ADL: activities of daily living; IADL: instrumental activities of daily living.

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Panza et al. drome of cognitive decline. Recent history of depression is associated with increased incidence of AD.18 Individuals with late-life depression and transient cognitive impairment frequently develop AD or VaD within a few years after the onset of depression.13 Together, these observations suggest that some latelife depressive syndromes may be early manifestations of dementing disorders.56 In contrast to this theory, depression may represent an independent risk factor predisposing to dementing disorders,18 even when depressive symptoms occur more than 10 years before the onset of dementia.57 Lifetime history of depression increases the risk of AD, regardless of the presence or absence of family history of dementing disorders,58 and depression may be also a risk factor for VaD.59 Moreover, the findings reviewed suggested that in primary MDD, the task is to figure out if the cognitive impairment is reversible or progressive in nature.50,51,53 In primary MCI, the task may be to figure out if depressive symptoms or a particular depressive pattern may predict progression to dementia. The findings from the ILSA showed that higher depressive symptoms at baseline (moderate or high depressive symptoms: GDS-30 ⱖ10 points) were not associated with the development of incident MCI60 or the progression of patients with MCI to dementia.61 At present, only in the CHS Cognition Study, the development of MCI was associated cross-sectionally with racial and constitutional factors, CVD, and measurements of cognition and depression.62 Very recently, the CHS Cognition Study confirmed these findings in a prospective study in which depressive symptoms at baseline (moderate or high depressive symptoms: CES-D ⱖ8 points) were associated with increased risk of MCI, and this association was independent of underlying vascular disease.63 In a cohort of cognitively normal elderly subjects without depression at recruitment, individuals in the depression cohort (GDS-15 ⱖ6 points) were at significantly increased risk of subsequent incident MCI, and a synergistic interaction between depression and APOE genotype was also found64 (Table 5). The findings from the ILSA suggested that depression and MCI may cooccur but failed to demonstrate a causal link between depressive symptoms and incident MCI,60 at least in a shorter follow-up. A possible role of depressive symptoms

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was recently evaluated in preclinical AD,65 suggesting that depressive symptoms may be a part of the preclinical phase of dementia. Furthermore, Wilson et al., in two cohort studies (the Religious Order Study and the Rush Memory and Aging Project) found that the risk of MCI increased by about 2% for each one-unit increase on an indicator of the tendency to experience psychological distress. Depressive symptoms evaluated with the 10item CES-D were also related to risk of MCI but not after controlling for distress score66 (Table 5). Furthermore, only among the participants from the Religious Order Study, depressive symptoms did not increase in those who subsequently developed MCI in a 13-year follow-up. However, the sample was very mildly depressed at baseline (mean 10item CES-D ⫾ SD: 1.0 ⫾ 1.5), and the participants were all highly educated.67 In the ILSA, depressive symptoms also failed to predict the conversion of MCI to dementia.61 Nonetheless, these findings are in contrast with those of another recent study in which patients with MCI and depression are at more than twice the risk of developing AD as those without depression68 (Table 5). However, in this study, a clinical diagnosis of depressive disorder (DSM-IV) was performed, and the subjects were from a community general hospital and not from a populationbased study. Furthermore, the results of the ILSA confirmed those of another recent study in which patients with MCI who had concurrent depression did not have an increased risk of incident AD, when compared with nondepressed patients with MCI.69 More recently, in a Polish study, multipledomain patients with aMCI had significantly higher MADRS baseline scores relative to single domain aMCI, and after a mean 3-year follow-up period, more severe depression (higher MADRS score) at baseline was a significant predictor for progression to dementia.70 On the contrary, in a French study, no difference was found in the prevalence of depressive symptoms (MADRS scores) between subjects with MCI converted to dementia and those who did not. Of the patients with apathy at baseline, 15.1% developed AD in comparison with 6.9% of the nonapathetic patients71 (Table 5). Furthermore, other recent data suggested that the anxiety-related or motivational (apathetic) symptoms of depression may be relevant to MCI

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Depression and Predementia Syndromes

TABLE 5.

Principal Studies Examining the Possible Role of Depressive Symptoms or Syndromes in Predicting Incident Mild Cognitive Impairment (MCI) and Its Progression to Dementia

References Risk of incident MCI Barnes et al.63

Geda et al.64

Panza et al.60

Wilson et al.66

Risk of progression from MCI to AD or dementia Modrego et al.68

Robert et al.71

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Setting and Study Design

Subjects

Tools, Procedure, or Diagnostic Criteria

Reported Risk of Incident MCI or Its Progression to Dementia in Relation to Depressive Symptoms or Depression at Baseline

Cross-sectional and 2,220 subjects from 4 U.S. MCI criteria: clinical diagnosis Low depressive symptoms: unadjusted OR: 1.38, 95% CI: according to Petersen’s communities aged 65 longitudinal, 1.03–1.85 criteria without intact years or older population IADL; depressive symptoms Moderate or high depressive based (6 years) symptoms: unadjusted OR: measured with the CES-D 2.20, 95% CI: 1.59–3.03 These associations were diminished only slightly by adjustment for vascular disease measures and demographics 840 subjects from primary MCI criteria: clinical diagnosis HR: 2.2; 95% CI: 1.2–4.1 (after Longitudinal, adjusting for possible according to Petersen’s care clinic, median age hospital based counfounders) criteria without (range) 77 (50–98) (3.5 years) HR: 5.1; 95% CI, 1.9–13.6) modifications; depressive (interaction between APOE symptoms measured with genotype ⑀3/⑀4 or ⑀4/⑀4 and the GDS-15 depression) RR: 1.25; 95% CI: 0.85–1.84 MCI criteria: 1.5 SDs below Cross-sectional and 2,963 subjects from mean age- and educationpopulation-register longitudinal, adjusted on the MMSE and (including institutions) population 10th percentile below ageaged from 65 to 84 based (3.5 years) and education-adjusted on years memory test, without SMC and intact ADL/IADL); depressive symptoms measured with the GDS-30 MCI criteria: clinical diagnosis RR: 1.06; 95% CI: 1.002–1.120 1,256 subjects from Longitudinal, RR: 1.02; 95% CI: 0.96–1.09 according to Petersen’s population-register; population (after adjusting for criteria; depressive mean ⫾ SD age: 78.6 ⫾ based (12 years) psychological distress score) symptoms measured with 7.6 years the 10-item CES-D

RR: 2.6; 95% CI: 1.8–3.6 aMCI criteria: clinical diagnosis according to Petersen’s criteria without modifications; major depression was carried out by means of a half-hour structured interview to elicit at least 5 depressive symptoms according to the DSM-IV criteria After a 1-year follow-up, 10.2% of aMCI criteria: patients with Cross-sectional and 251 patients with aMCI patients developed AD and memory complaints and from the referral longitudinal, 194 did not develop AD. There patients presenting at least populations of the 14 hospital based were no differences at baseline one error to the MMSE centers with memory (1 year) between the two groups for three word recall, or a consultation facilities; MADRS total score. Of the score lower than 29 to the aged 58 years and older patients with apathy at Isaac-set test; depressive baseline, 15.1% developed AD symptoms measured with in comparison with 6.9% of the MADRS. Apathy was the non-apathetic patients assessed with the Apathy Inventory (Continued) Longitudinal, hospital based (3 years)

114 patients with aMCI from a community general hospital; mean ⫾ SD age: 72.8 ⫾ 5.3 years

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Panza et al.

TABLE 5.

(Continued)

References Gabryelewicz et al.70

Teng et al.73

Palmer et al.75

Panza et al.61

Houde et al.76

Setting and Study Design

Subjects

Tools, Procedure, or Diagnostic Criteria

Reported Risk of Incident MCI or Its Progression to Dementia in Relation to Depressive Symptoms or Depression at Baseline

MCI criteria: clinical diagnosis After 3 years of follow-up, multiple domain patients with according to Petersen’s aMCI had significantly higher criteria, with a MADRS baseline scores relative subclassification in single to single domain aMCI and and multiple domain aMCI; more severe depressive depressive symptoms symptoms at baseline in measured with the MADRS multiple domain patients with aMCI were a significant predictor for progression to dementia MCI criteria: clinical diagnosis Subjects with MCI progressing to 51 patients with aMCI Longitudinal, AD had a significantly higher according to modified from a tertiary care hospital based prevalence of neuropsychiatric Petersen’s criteria with 1.5 center; mean ⫾ SD age: (2 years) symptoms than subjects who SD below age- and 73.9 ⫾ 6.7 years remained stable or improved education-adjusted norms (100 vs. 59%). In particular, on neuropsychological test depression (67 vs. 31%) and scores; depressive apathy (50 vs. 18%) were more symptoms measured with common in subjects who were the NPI later diagnosed with AD MCI criteria: 1 SD below age- Mood-related depressive Cross-sectional and In a population of 628 symptoms RR: 0.9; 95% CI: and education-adjusted persons aged 75 years longitudinal, 0.6–1.5 norms on MMSE score; and older, 47 persons population Motivation-related depressive aMCI criteria: objective fulfilled the criteria of based (3 years) symptoms RR: 1.1; 95% CI: impairment in episodic MCI (amnestic or 0.7–1.8 memory task but normal multidomains) and 185 functioning on visuospatial were cognitively and language tasks; unimpaired at baseline multidomains MCI criteria: impairment in two or more of the episodic memory, language, and visuospatial domains; depressive and anxiety symptoms were measured with CPRS MCI criteria: 1.5 SDs below RR: 1.42; 95% CI: 0.48–4.23 Cross-sectional and 2,963 subjects from mean age- and educationpopulation-register longitudinal, adjusted on the MMSE and (including institutions) population 10th percentile below ageaged from 65 to 84 based (3.5 years) years and education-adjusted on memory test, without SMC and intact ADL/IADL); depressive symptoms measured with the GDS-30 HR: 1.07; 95% CI: 0.99–1.15 aMCI criteria: clinical 60 patients with aMCI Longitudinal, diagnosis according to from a tertiary care hospital based Petersen’s criteria without center; mean ⫾ SD age: (4.3 years) modifications; depressive 74.5 ⫾ 6.5 years symptoms measured with the GDS-30 Longitudinal, hospital based (3 years)

105 patients with MCI

IADL: instrumental activities of daily living; CES-D: Center for Epidemiological Studies Depression Scale 10-item questionnaire; OR: odds ratio; HR: hazard ratio; ADL: activities of daily living; RR: relative risk; MMSE: Mini-mental State Examination; SMC: subjective memory complaint; CPRS: Comprehensive Psychopathological Rating Scale.

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Depression and Predementia Syndromes and progression of MCI to dementia.72–75 In fact, in 51 subjects with MCI assessed for neuropsychiatric symptoms using the NPI and followed for an average of 2 years, subjects progressing to AD had a significantly higher prevalence of psychopathology than subjects who remained stable or improved (100% versus 59%). In particular, depression (67% versus 31%) and apathy (50% versus 18%) were more common in subjects who were later diagnosed with AD.73 Robert et al.,74 in a longitudinal study with a 3-year follow-up on 214 patients with aMCI with depressive symptoms, found that the risk of progression to AD was significantly higher for patients with lack of interest, one dimension of apathy. Findings from the population-based Kungsholmen project suggested that subjects with MCI plus anxiety symptomatology had an increased risk of progressing to AD over 3 years compared with that of subjects with MCI and without anxiety problems. Furthermore, depressed mood was predictive of AD in subjects with normal levels of baseline cognition and being frequent in subjects with MCI75 (Table 5). In 60 patients with MCI from a hospital-based study with a 4.3year follow-up, simple presence or absence of depression at referral (moderate or high depressive symptoms: GDS-30 ⱖ10 points) did not predict progression of MCI to AD. Positive answers to specific GDS-30 questions referring to a pattern of melancholia and the persistence of depression over 2–3 years significantly predicted cognitive deterioration leading to AD76 (Table 5). At present, for depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia seem to be conflicting. However, future work will have to assess participants using more comprehensive screening tools for depressive symptoms, combined with instruments that show good validity for examination of anxiety and apathy. In patients with MCI with these mood symptoms, executive functions seem especially vulnerable.77 More cross-sectional and longitudinal studies would help to clarify whether this group of dysexecutive patients with MCI plus anxietyrelated or apathetic symptoms of depression should be considered as having subclinical late-life depression or at higher risk of progression to dementia, and particularly AD.

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DEPRESSION AND PREDEMENTIA SYNDROMES: POSSIBLE MECHANISMS Depression and MCI: Shared Risk Factors or Confounding At present, the mechanisms on the possible role of depression and depressive symptoms in the development of predementia syndromes or their progression to dementia are still under investigation. One possibility is that depression and predementia syndromes share the same risk factors or confounding. In fact, additional factors, genetic, environmental, or both may lead to the genesis of both MCI and depression (Fig. 1). Current etiological models of latelife depression and cognitive decline focus on the potential role of vascular risk factors and suggested possible opportunities for specific prevention and intervention strategies in high-risk populations.2 In fact, some late-life depressive syndromes might predispose, precipitate, or perpetuate by CVD, the so called “vascular depression” hypothesis.78 This notion is based on the comorbidity of depressive syndromes with cerebrovascular lesions and cerebrovascular risk factors and on the fact that depression often develops after a stroke.14 Elderly people with vascular depression have greater disability and cognitive impairment than those who are depressed but who do not have comorbid vascular stigmata.14 Furthermore, previous studies have shown a correlation between MCI and vascular risk factors, such as hypertension, total cholesterol, and coronary artery disease.2 However, in the ILSA, no sociodemographic variables or vascular risk factors modified the association between depressive symptoms and incident MCI or between depressive symptoms and conversion to dementia.60,61 Furthermore, in the ILSA, vascular disease or vascular risk factors did not have any impact on the onset of depressive symptoms in both cognitively stable patients with MCI and in patients with MCI who reverted to normal cognition after a 3.5-year follow-up.35 Possibly, a longer follow-up would reveal that vascular factors might influence the incidence of MCI in depressed patients, its progression to dementia, or the onset of mood disturbances in patients with MCI. Butters et al.18 suggested two possible pathways linking depression, vascular disease, MCI,

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Panza et al.

FIGURE 1.

Synopsis of the Principal Hypotheses on the Possible Mechanisms Linking Depression to Mild Cognitive Impairment (MCI)

and dementia: 1) individuals who accumulate AD neuropathology over many years along with cooccurring CVD, which damages the frontostriatal circuitry, leading to late-life depression. The total neuropathologic burden, combined with depressed mood, lowers brain reserve capacity, leads to expression of MCI (e.g., memory and executive dysfunction) earlier than otherwise would be the case, and, given the underlying neuropathology, progresses to AD along with cooccurring CVD and 2) individuals who develop CVD (with variable neuropathologic burden) leading to late-life depression and MCI (e.g., executive dysfunction), which will follow the course of the underlying CVD. However, at present, epidemiologic studies suggest that the possible association between depressive symptoms and MCI seems not attributable to vascular disease or risk,60,61,63 and several other hypotheses on the underlying mechanism have been proposed (Fig. 1). Coexistence of Depression and MCI Another hypothesis is that development of late-life depressive symptoms may reflect an underlying neu-

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ropathologic condition that will develop also cognitive decline over time. Therefore, depressive symptoms without clinically significant cognitive impairment may be the early signs of a neurodegenerative disease56 (Fig. 1). Alternatively, depression may “unmask” the clinical manifestations of MCI in individuals with limited cognitive reserve,79 or depressive symptoms may overlap to some extent with the symptoms of cognitive decline (Fig. 1). It is also possible that individuals with some degree of cognitive decline may develop depression as a reaction to the cognitive symptoms (Fig. 1). In fact, some evidence suggested that patients with MDD reported in self and observer ratings cognitive problems exceeded neuropsychological deficits in standardized tests, and these results could be additionally influenced by patients negative self-perception.80 Furthermore, some findings suggest that anxiety or apathetic symptoms of depression in MCI may be a response to the initial phases of cognitive impairment in neurodegeneration,71–74 whereas mood-related depressive symptoms may be a preclinical sign of AD related to the neuropathologic mechanism, present even in individuals with prodromal AD who have no detectable

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Depression and Predementia Syndromes cognitive impairment.75 Several other hypotheses may explain the relationship between depression and predementia syndromes. One possibility is that depression may be a causal factor leading to hippocampal damage through a glucocorticoid cascade19 (Fig. 1). In fact, older adults with high or rising cortisol levels during 5 years had poorer memory and greater hippocampal atrophy.81 Depression could produce degenerative lesions in the hippocampus mediated by the excess of glucocorticoids,82 neuronal loss in the aminergic nuclei of the brainstem,18 and a fall in the levels of noradrenaline and serotonin in the cerebral cortex and hippocampus.18 Butters et al.18 suggested two possible pathways linking depression, hypothalamic-pituitary-adrenal-stress axis, MCI, and dementia: 1) individuals who develop depression at any point and who experience depression-related neuropathology (e.g., hippocampal volume loss) that results in MCI that is stable (unless they experience additional depressive episodes) and 2) individuals who accumulate AD neuropathology over many years and who develop late-life depression (related or unrelated to AD pathology), that lowers brain reserve capacity, and results in expression of MCI earlier than otherwise would be the case, and given the underlying neuropathology, progress to AD. An important implication of this hypothesis is that an intervention targeting depression may lead to primary prevention of MCI and subsequent dementia.

Depression and MCI: Interaction With a Genetic Susceptibility Factor Another hypothesis is a possible interaction in which depression leads to cognitive decline only in the presence of a genetic susceptibility factor (Fig. 1). In fact, a recent study found evidence of a synergistic interaction between APOE genotype and depression.63 There also may be a genetic link between depressive symptoms and dementia in some patients. For example, a study of women at high risk of carrying the presenilin 1 mutation for dementia showed that carriers of this mutation had significantly more depressive symptoms than noncarriers and were more likely to have sought help from a psychiatric professional.83 Of course, all these hypotheses and other possible mechanisms are not mutually exclusive,18 may act in com-

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bination, and need clinical or experimental confirmation in the near future.

CONCLUSIONS Prevalence rates of depressive syndromes or symptoms vary widely among studies, as a result of different diagnostic criteria and operational definitions of depression (MDD versus depressive symptoms) and different sampling and assessment procedures. In fact, although hospital-based studies on MCI reported a higher prevalence of depressive symptoms (median value: 44.3%), populationbased studies reported a prevalence of 3%– 63.3% (median value: 15.7%) for depression among patients with MCI. Avoiding a subclassification for study setting, the median value of depressive symptoms in patients with MCI was, therefore, 34%. At present, incidence of depressive symptoms varied from 11.7 to 26.6 per 100 person-years in the very few hospital-based and populationbased studies available, suggesting the need for additional research in this area to describe also prevalence and incidence of depressive symptoms or syndromes in MCI subtypes. Furthermore, persistent cognitive deficits in the context of MDD are a significant clinical concern because they may reflect underlying structural changes that increase an individual’s risk of progression to AD or another form of dementia.13 The tripled prevalence of depression of patients with MCI in hospital-based samples versus population-based samples may reflect different referral patterns, selection criteria and tools, and different stages of cognitive decline. Nonetheless, in the studies reviewed, prevalence and incidence estimates of depressive symptoms in MCI had important limitations, because it was impossible to establish a precise link between MCI and neuropsychiatric symptoms. Future studies should include a standardization of settings, diagnostic criteria for predementia, and depression syndromes or the means of collecting depressive symptoms. At present, for depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia seem to be conflicting. Converging evidence suggests that late-onset depressive symptoms or syndromes often are a prodrome of cogni-

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Panza et al. tive decline. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, the level of education, the setting (population based versus hospital based), and methodological differences (measurement of depressive symptoms or diagnosis of depressive disorders and level of depressive symptoms or particular patterns of depressive symptoms) may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Furthermore, self-report measures could overestimate MCI in patients with depression as some of the reported cognitive impairment may be related to negative self-appraisal.80 Examining the reviewed measures of risk of incident MCI or its progression to dementia (Table 5), we noted that all are ⬎1, suggesting that discrepancy among study findings may be attributable also to random variation/low power. The development of universal diagnostic tools or more precise measurements of both depressive and cognitive symptoms could help the researchers to overcome this methodological bias, avoiding to report such disparate findings. In particular, a battery of tests with sensitivity to change over time could be developed for the assessment of mood and behavioral symptoms in clinical MCI studies, with a briefer screening version that could be used in epidemiologic studies and in primary care settings, combined with instruments with good validity for examination of anxiety and apathy in depression. These observations suggested that late-life depressive syndromes may be early manifestations of dementing disorders, suggesting that depressive symptoms might be included in MCI diagnostic criteria. In fact, in the proceedings of the 2003 NIMH conference on this topic, Steffens et al.3 suggested specifically that research is needed to clarify whether mood symptoms might be included in diagnostic criteria sets (e.g., MCI and mood disorder), act as a modifier (e.g., MCI with depression), be excluded from the MCI diagnosis, or be seen as one of two distinct but not mutually exclusive diagnoses (e.g., MCI and major or minor depression). Furthermore, the European Consortium on Alzheimer’s Disease Working Group on MCI has very recently proposed that psychological and behavioral symptoms have to be taken in account too and should not systematically be an

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“exclusion criteria” for the diagnosis.10 Subjects may have depressive symptoms related to cognitive impairment or to the underlying process.13 Of course, it also should be clarified that this continuum would only apply in particular subgroups of elders. In fact, depressive symptoms may be high both in patients with MCI who remained dementia-free and in patients with MCI who progressed to dementia or AD. In the first group of subjects, MCI could be related to an underlying psychiatric disorder, and in the second group, MCI and depression may be associated with neurodegeneration. In conclusion, the critical question is how the presence of depression modifies the risk of incident MCI or progression of MCI to dementia. Central to this question is determining the extent to which depression is a true risk factor versus an early symptom occurring in the prodromal phase of dementia, particularly AD (e.g., aMCI). Substantial support exists for both hypotheses, and they are not mutually exclusive. Some findings suggest that when depressive and cognitive symptoms appear close in time they likely arise from common neuropathologic processes.18This is an important competing hypothesis to the concept of depression as a risk factor for progression of MCI to dementia. Therefore, assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and AD,56 arguing that the underlying neuropathologic condition that causes MCI or dementia also causes depressive symptoms, rather than depressive symptoms causing or exacerbating MCI. In this picture, at least in certain subsets of elderly patients (e.g., dysexecutive MCI plus anxiety related or apathetic symptoms of depression), late-life depression, MCI, and dementia could represent a possible clinical continuum with indefinite bounds.

This work was supported by the Italian Longitudinal Study on Aging (ILSA) (Italian National Research Council—CNR-Targeted Project on Ageing— grants 9400419PF40 and 95973PF40). The CNR had no further role in study design; in the collection, analysis, and interpretation of data; in writing of the report; and in the decision to submit the paper for publication.

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Depression and Predementia Syndromes References 1. Panza F, D’Introno A, Colacicco AM, et al: Current epidemiology of mild cognitive impairment and other predementia syndromes. Am J Geriatr Psychiatry 2005; 13:633– 644 2. Panza F, D’Introno A, Colacicco AM, et al: Cognitive frailty: Predementia syndrome and vascular risk factors. Neurobiol Aging 2006; 27:933–940 3. Steffens DC, Otey E, Alexopoulos GS, et al: Perspectives on depression, mild cognitive impairment, and cognitive decline. Arch Gen Psychiatry 2006; 63:130 –138 4. Hughes CP, Berg L, Danziger WL, et al: A new clinical scale for the staging of dementia. Br J Psychiatry 1982; 140:566 –572 5. Petersen RC, Smith GE, Waring SC, et al: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303–308 6. Petersen RC, Doody R, Kurz A, et al: Current concepts in mild cognitive decline. Arch Neurol 2001; 58:1985–1992 7. Winblad B, Palmer K, Kivipelto M, et al: Mild cognitive impairment– beyond controversies, towards a consensus: report of the International Working Group on mild cognitive impairment. J Intern Med 2004; 256:240 –246 8. Petersen RC, Smith GE, Waring SC, et al: Aging, memory, and mild cognitive impairment. Int Psychogeriatr 1997; 9:65– 69 9. Gauthier S, Reisberg B, Zaudig M; International Psychogeriatric Association Expert Conference on mild cognitive impairment: Mild cognitive impairment. Lancet 2006; 367:1262–1270 10. Portet F, Ousset PJ, Visser PJ, et al; MCI Working Group of the European Consortium on Alzheimer’s Disease (EADC): Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure report of the MCI Working Group of the European Consortium on Alzheimer’s Disease. J Neurol Neurosurg Psychiatry 2006; 77:714 –718 11. American Psychiatric Association Committee on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders. 4th edition (DSM-IV). Washington, DC, American Psychiatric Association, 1994 12. World Health Organization: International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). Chapter V, categories F00 –F99: Mental, Behavioural, and Developmental Disorders, Clinical Description and Diagnostic Guidelines. Geneva, Switzerland, World Health Organization, 1992 13. Potter GG, Steffens DC: Contribution of depression to cognitive impairment and dementia in older adults. Neurologist 2007; 13: 105–117 14. Alexopoulos GS: Depression in the elderly. Lancet 2005; 365: 1961–1970 15. Wragg RE, Jeste DV: Overview of depression and psychosis in Alzheimer’s disease. Am J Psychiatry 1989; 146:577–589 16. Sobin C, Sacheim HA: Psychomotor symptoms of depression. Am J Psychiatry 1997; 154:4 –17 17. Olin JT, Schneider LS, Katz IR, et al: Provisional diagnostic criteria for depression of Alzheimer’s disease. Am J Geriatr Psychiatry 2002; 10:125–128 18. Butters MA, Young JB, Lopez O, et al: Pathways linking late-life depression to persistent cognitive impairment and dementia. Dialogues Clin Neurosci 2008; 10:345–357 19. Sapolsky RM: Depression, antidepressants, and the shrinking hippocampus. Proc Natl Acad Sci USA 2001; 98:12320 –12322 20. First MB, Spitzer RL, Gibbon M, et al: Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I), Clinician Version, Administration Booklet. Washington, DC: American Psychiatric Press, 1997

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21. Lyness JM, King DA, Cox C, et al: The importance of subsyndromal depression in older primary care patients: prevalence and associated functional disability. J Am Geriatr Soc 1999; 47:647– 652 22. Gallo JJ, Rabins PV, Lyketsos LG, et al: Depression without sadness: functional outcomes of nondysphoric depression in later life. J Am Geriatr Soc 1997; 45:570 –578 23. Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982– 83; 17:37– 49 24. Debruyne H, Van Buggenhout M, Le Bastard N, et al: Is the geriatric depression scale a reliable screening tool for depressive symptoms in elderly patients with cognitive impairment? Int J Geriatr Psychiatry 2009; 24:556 – 662 25. Radloff LS: The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Measurement 1977; 1:385– 401 26. Irwin M, Artin KH, Oxman MN: Screening for depression in the older adult: criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D). Arch Intern Med 1999; 159:1701–1704 27. Beck AT, Steer RA, Brown GK: Beck Depression Inventory-II Manual. San Antonio, TX: Psychological Corporation, 1996 28. Alexopoulos GS, Abrams RC, Young RC, et al: Cornell scale for depression in dementia. Biol Psychiatry 1988; 23:271–284 29. Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308 –2314 30. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56 – 62 31. Montgomery SA, Asberg M: A new depression scale designed to be sensitive to change. Br J Psychiatry 1979; 134:382–389 32. Asberg M, Montgomery SA, Perris C, et al: A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978; suppl 271:5–27 33. Goldberg D, Bridges K, Duncan-Jones P, et al: Detecting anxiety and depression in general medical settings. BMJ 1988; 297:897– 899 34. Tariot PN: CERAD behavior rating scale for dementia. Int Psychogeriatr 1996; 8(suppl 3):317–320 35. Solfrizzi V, D’Introno A, Colacicco AM, et al: Italian Longitudinal Study on Aging Working Group. Incident occurrence of depressive symptoms among patients with mild cognitive impairment— the Italian Longitudinal Study on Aging. Dement Geriatr Cogn Disord 2007; 24:55– 64 36. Lyketsos CG, Lopez O, Jones B, et al: Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002; 288:1475– 1483 37. Chan DC, Kasper JD, Black BS, et al: Prevalence and correlates of behavioral and psychiatric symptoms in community-dwelling elders with dementia or mild cognitive impairment: the Memory and Medical Care Study. Int J Geriatr Psychiatry 2003; 18:174 –182 38. Forsell Y, Palmer K, Fratiglioni L: Psychiatric symptoms/syndromes in elderly persons with mild cognitive impairment. Data from a cross-sectional study. Acta Neurol Scand 2003; suppl 179:25–28 39. Kumar R, Jorm AF, Parslow RA, et al: Depression in mild cognitive impairment in a community sample of individuals 60 – 64 years old. Int Psychogeriatr 2006; 18:471– 480

Am J Geriatr Psychiatry 18:2, February 2010

Copyright © American Association for Geriatric Psychiatry. Unauthorized reproduction of this article is prohibited.

Panza et al. 40. Kumar R, Parslow RA, Jorm AF, et al: Clinical and neuroimaging correlates of mild cognitive impairment in a middle-aged community sample: the personality and total health through life 60⫹ study. Dement Geriatr Cogn Disord 2006; 21:44 –50 41. Muangpaisan W, Intalapaporn S, Assantachai P: Neuropsychiatric symptoms in the community-based patients with mild cognitive impairment and the influence of demographic factors. Int J Geriatr Psychiatry 2008; 23:699 –703 42. Copeland MP, Daly E, Hines V, et al: Psychiatric symptomatology and prodromal Alzheimer’s disease. Alzheimer Dis Assoc Disord 2003; 17:1– 8 43. Hwang TJ, Masterman DL, Ortiz F, et al: Mild cognitive impairment is associated with characteristic neuropsychiatric symptoms. Alzheimer Dis Assoc Disord 2004; 18:17–21 44. Geda YE, Smith GE, Knopman DS, et al: De novo genesis of neuropsychiatric symptoms in mild cognitive impairment. Int Psychogeriatr 2004; 16:51– 60 45. Lopez OL, Becker JT, Sweet RA: Non-cognitive symptoms in mild cognitive impairment subjects. Neurocase 2005; 11:65–71 46. Gabryelewicz T, Styczynska M, Pfeffer A, et al: Prevalence of major and minor depression in elderly persons with mild cognitive impairment: MADRS factor analysis. Int J Geriatr Psychiatry 2004; 19:1168 –1172 47. Rozzini L, Vicini Chilovi B, Conti M, et al: Neuropsychiatric symptoms in amnestic and nonamnestic mild cognitive impairment. Dement Geriatr Cogn Disord 2008; 25:32–36 48. Ellison JM, Harper DG, Berlow Y, et al: Beyond the “C” in MCI: noncognitive symptoms in amnestic and non-amnestic mild cognitive impairment. CNS Spectr 2008; 13:66 –72 49. Feldman H, Scheltens P, Scarpini E, et al: Behavioral symptoms in mild cognitive impairment. Neurology 2004; 62:1199 –1201 50. Reischies FM, Neu P: Comorbidity of mild cognitive disorder and depression—a neuropsychological analysis. Eur Arch Psychiatry Clin Neurosci 2000; 250:186 –193 51. Butters MA, Becker JT, Nebes RD, et al: Changes in cognitive functioning following treatment of late-life depression. Am J Psychiatry 2000; 157:1949 –1954 52. Adler G, Chwalek K, Jajcevic A: Six-month course of mild cognitive impairment and affective symptoms in late-life depression. Eur Psychiatry 2004; 19:502–505 53. Lee JS, Potter GG, Wagner HR, et al: Persistent mild cognitive impairment in geriatric depression. Int Psychogeriatr 2007; 19: 125–135 54. O’Brien JT, Lloyd A, McKeith I, et al: A longitudinal study of hippocampal volume, cortisol levels, and cognition in older depressed subjects. Am J Psychiatry 2004; 161:2081–2090 55. Li YS, Meyer JS, Thornby J: Longitudinal follow-up of depressive symptoms among normal versus cognitively impaired elderly. Int J Geriatr Psychiatry 2001; 16:718 –727 56. Chen P, Ganguli M, Mulsant BH, et al: The temporal relationship between depressive symptoms and dementia: a community-based prospective study. Arch Gen Psychiatry 1999; 56:261–266 57. Steffens DC, Plassman BL, Helms MJ, et al: A twin study of late-onset depression and apolipoprotein E ⑀4 as risk factors for Alzheimer’s disease. Biol Psychiatry 1997; 41:851– 856 58. van Duijn CM, Clayton DG, Chandra V: Interaction between genetic and environmental risk factors for Alzheimer’s disease: a reanalysis of case-control studies. Genet Epidemiol 1994; 11:539 –551 59. Canadian Study of Health and Aging Working Group: The incidence of dementia in Canada. Neurology 2000; 55:66 –73 60. Panza F, D’Introno A, Colacicco AM, et al: Italian Longitudinal Study on Aging Working Group. Depressive symptoms, vascular risk factors and mild cognitive impairment. The Italian

Am J Geriatr Psychiatry 18:2, February 2010

longitudinal study on aging. Dement Geriatr Cogn Disord 2008; 25:336 –346 61. Panza F, Capurso C, D’Introno A, et al: Impact of depressive symptoms on the rate of progression to dementia in patients affected by mild cognitive impairment. The Italian longitudinal study on aging. Int J Geriatr Psychiatry 2008; 23:726 –734 62. Lopez OL, Jagust WJ, Dulberg C, et al: Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 2003; 60:1394 –1399 63. Barnes DE, Alexopoulos GS, Lopez OL, et al: Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Arch Gen Psychiatry 2006; 63:273–279 64. Geda YE, Knopman DS, Mrazek DA, et al: Depression, apolipoprotein E genotype, and the incidence of mild cognitive impairment: a prospective cohort study. Arch Neurol 2006; 63:435– 440 entity. J Intern Med 2004; 256:183–194 65. Berger AK, Fratiglioni L, Forsell Y, et al: The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study. Neurology 1999; 53:1998 –2002 66. Wilson RS, Schneider JA, Boyle PA, et al: Chronic distress and incidence of mild cognitive impairment. Neurology 2007; 68: 2085–2092 67. Wilson RS, Arnold SE, Beck TL, et al: Change in depressive symptoms during the prodromal phase of Alzheimer disease. Arch Gen Psychiatry 2008; 65:439 – 446 68. Modrego PJ, Ferrandez J: Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: a prospective cohort study. Arch Neurol 2004; 61:1290 –1293 69. Rozzini L, Vicini Chilovi B, Trabucchi M, et al: Depression is unrelated to conversion to dementia in patients with mild cognitive impairment. Arch Neurol 2005; 62:505 70. Gabryelewicz T, Styczynska M, Luczywek E: The rate of conversion of mild cognitive impairment to dementia: predictive role of depression. Int J Geriatr Psychiatry 2007; 22:563–567 71. Robert PH, Berr C, Volteau M, et al: The Pre´AL study: apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer’s disease: a one-year follow-up study. Clin Neurol Neurosurg 2006; 108:733–736 72. Ready RE, Ott BR, Grace J, et al: Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease. Am J Geriatr Psychiatry 2003; 11:222–228 73. Teng E, Lu PH, Cummings JL: Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer’s disease. Dement Geriatr Cogn Disord 2007; 24:253–259 74. Robert PH, Berr C, Volteau M, et al: Importance of lack of interest in patients with mild cognitive impairment. Am J Geriatr Psychiatry 2008; 16:770 –776 75. Palmer K, Berger AK, Monastero R, et al: Predictors of progression from mild cognitive impairment to Alzheimer disease. Neurology 2007; 68:1596 –1602 76. Houde M, Bergman H, Whitehead V, et al: A predictive depression pattern in mild cognitive impairment. Int J Geriatr Psychiatry 2008; 23:1028 –1033 77. Hudon C, Belleville S, Gauthier S: The association between depressive and cognitive symptoms in amnestic mild cognitive impairment. Int Psychogeriatr 2008; 20:710 –723 78. Alexopoulos GS, Meyers BS, Young RC, et al: Clinically defined vascular depression. Am J Psychiatry 1997; 154:562–565 79. Jorm AF, van Duijn CM, Chandra V; EURODEM Risk Factors Research Group. Psychiatric history and related exposures as risk

115

Copyright © American Association for Geriatric Psychiatry. Unauthorized reproduction of this article is prohibited.

Depression and Predementia Syndromes factors for Alzheimer’s disease: a collaborative re-analysis of casecontrol studies. Int J Epidemiol 1991; 20(suppl 2):S43–S47 80. Lahr D, Beblo T, Hartje W: Cognitive performance and subjective complaints before and after remission of major depression. Cogn Neuropsychiatry 2007; 12:25– 45 81. Lupien SJ, de Leon M, de Santi S, et al: Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998; 1:69 –73

116

82. Steffens DC, Payne ME, Greenberg DL, et al: Hippocampal volume and incident dementia in geriatric depression. Am J Geriatr Psychiatry 2002; 10:62–71 83. Ringman JM, Diaz-Olavarrieta C, Rodriguez Y, et al: Female preclinical presenilin-1 mutation carriers unaware of their genetic status have higher levels of depression than their nonmutation carrying kin. J Neurol Neurosurg Psychiatry 2004; 75:500 –502

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