Cognitive impairment is estimated to exist in 17% 36% of

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1 REVIEW ARTICLE Contribution of Depression to Cognitive Impairment and Dementia in Older Adults Guy G. Potter, PhD, and David C. Steffens, MD, MHS Background: The objective of this review is to provide information for clinicians regarding current research and opinions on the association of depression to conditions of cognitive impairment and dementia. We also intend to integrate this current research and thinking into strategies for the assessment and treatment of depression in the context of cognitive impairment. Review Summary: Depression is highly prevalent in mild cognitive impairment and most dementias. It may be a risk factor for the subsequent development of dementia and in some conditions may be a prodromal symptom. It is important to detect and effectively treat depression because the comorbidity of depression and cognitive impairment is associated with greater cognitive and functional decline and higher rates of institutionalization. Depression often can be differentiated from Alzheimer disease and other dementias based on characteristics of clinical history and presentation. Screening of depression and cognitive impairment will help characterize the presence and severity of these conditions, but limitations in screening approaches may necessitate comprehensive assessment in complex cases where differential diagnosis is important to treatment planning. Conclusion: Although depression and cognitive impairment are important issues in the treatment of older adults, there are particular risks when they occur together. Appropriate assessment and screening can help guide the clinician to appropriate and timely interventions. Pharmacologic and nonpharmacologic treatment approaches are both efficacious in reducing depression in cognitive impairment and dementia. Key Words: depression, cognitive impairment, dementia, Alzheimer disease, elderly (The Neurologist 2007;13: ) From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina. Support for the writing of this paper was provided by funding from the following grants from the National Institute of Mental Health: P50 MH60451, R01 MH54846, and K24 MH Reprints: Guy G. Potter, PhD, Assistant Professor of Psychiatry and Medicine, Duke University Medical Center, DUMC Box 3925, Durham, NC guy.potter@ duke.edu. Copyright 2007 by Lippincott Williams & Wilkins ISSN: /07/ DOI: /01.nrl a9 Cognitive impairment is estimated to exist in 17% 36% of adults over the age of 65 in the United States 1 and in many cases evolves to dementia. 2 Significant depressive symptoms are present in 15% 30% of older adults and are often comorbid with cognitive impairment and dementia. 3,4 Depression co-occurring with cognitive impairment or dementia has an additive effect on adverse outcomes for physical health, functional status, and mortality. 5 Debate continues about whether depression in either early or late life is a risk factor for dementia 6 8 or whether it is more accurately characterized as a prodrome of this condition. 9,10 Complicating this debate is the fact that depression among older adults often causes cognitive impairment in its own right. 11,12 Given that the personal and public costs of both depression and cognitive impairment are likely to increase along with the growing proportion of aged individuals in populations of the United States and other developed countries, it is important for clinicians to develop skills to detect and treat cognitive impairment and depression whether they occur separately or together. Depression co-occurring with cognitive impairment or dementia has an additive effect on adverse outcomes for physical health, functional status, and mortality. DEPRESSION Depression is a disorder of mood that produces sad feelings, negative thoughts, and disruptions of sleep, appetite, thinking, and energy level. A major depressive disorder is defined as 1 or more episodes of negative mood and sadness that are sufficient to interfere with daily living. 13 A dysthymic disorder is a chronic but less severe and disabling form of negative mood state. 13 Depression is nearly twice as prevalent in women as in men. 14 Although most clinicians diagnose depression based on a categorical approach like that in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV-TR; see Table 1), 13 it is important to recognize that any depressive symptoms that impair cognition or activities of daily living (ADLs) are clinically The Neurologist Volume 13, Number 3, May

2 Potter and Steffens The Neurologist Volume 13, Number 3, May 2007 TABLE 1. Comparison of Major Depressive Episode 13 and Provisional Criteria of Depression of Alzheimer Disease Major Depressive Episode A. Five (or more) of the following symptoms have been present during the same 2-wk period and represent a change from previous functioning Do not include symptoms that are clearly due to a general medical condition or mood-incongruent delusions or hallucinations Depression of AD A. Three (or more) of the following symptoms have been present during the same 2-wk period and represent a change from previous functioning: at least 1 of the symptoms is either (1) depressed mood or (2) decreased positive affect or pleasure Do not include symptoms that, in your judgment, are clearly due to a medical condition other than Alzheimer disease or are a direct result of non moodrelated dementia symptoms (eg, loss of weight due to difficulties with food intake) (1) Clinically significant depressed mood (eg, depressed, sad, hopeless, discouraged, tearful) (2) Decreased positive affect or pleasure in response to social contacts and usual activities (3) Social isolation or withdrawal (1) Depressed mood most of the day, nearly every day, as either indicated by subjective report or observation of others (2) Markedly diminished interest or pleasure in all or almost all activities most the day, nearly every day (either 1 or 2 are required) (3) Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day (4) Insomnia or hypersomnia nearly every day (4) Disruption in appetite (5) Psychomotor agitation or retardation nearly every day (5) Disruption in sleep (6) Fatigue or loss of energy nearly every day (6) Psychomotor changes (eg, agitation or retardation) (7) Feelings of worthlessness or excessive or inappropriate guilt nearly (7) Irritability every day (8) Diminished ability to think or concentrate (8) Fatigue or loss of energy (9) Recurrent thoughts of death, recurrent suicidal ideation without a (9) Feelings of worthlessness, hopelessness, or excessive or inappropriate specific plan, or a suicide attempt or a specific plan for committing guilt suicide (10) Recurrent thoughts of death, suicidal ideation, plan or attempt B. Does not meet criteria for a mixed episode. The symptoms are not E. All criteria are met for dementia of the Alzheimer type (DSM-IV-TR) better accounted for by bereavement C. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse or a medication) or a general medical condition (eg, hypothyroidism) D. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning Adapted from Olin et al. 66 F. The symptoms cause clinically significant distress or disruption in functioning G. The symptoms do not occur exclusively during the course of a delirium H. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse or a medication) I. 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 significant. 15 The prevalence of depression is influenced by factors like hospitalization, where it is estimated at nearly 50% for major and minor depression. 15 The prevalence rate of depression in nursing homes is approximately 25%. 16 For the purposes of the current review, the definition of depression subsumes major depression, dysthymia, and other subtypes of depression. Most research on neurocognitive deficits in depression has found that depressed individuals tend to have decreased performance relative to nondepressed control participants on a number of neuropsychological measures. 106 Depression and Neurocognitive Function Impairment in concentration and other thinking abilities is one of the key diagnostic criteria of depression. Most research on neurocognitive deficits in depression has found that depressed individuals tend to have decreased performance relative to nondepressed control participants on a number of neuropsychological measures. Experimental studies have found depressed individuals to be most prominently affected in the domains of executive function, 11,17 memory, 17,18 and processing speed, 19 results that are consistent with meta-analyses of the broader literature. 20,21 Increasing severity of depression and specific symptoms reflecting apathy both appear to have a particularly strong association to deficits in executive functions and information processing speed. 11,22 Deficits in executive functions, which broadly refer to a number of prefrontally mediated cognitive processes, such as selective attention, response inhibition, planning, and performance monitoring, are associated with worse acute 23 and long-term 24 treatment response and greater func Lippincott Williams & Wilkins

3 The Neurologist Volume 13, Number 3, May 2007 Contribution of Depression to Cognitive Impairment and Dementia tional disability 25 in depression. Deficits in cognitive performance occur most consistently among older individuals with a first onset of depression in late life, though some evidence suggests that memory deficits may be more pronounced among older individuals with early-onset depression. 26 Late-onset depression is more frequently characterized by medical comorbidity, whereas early-onset depression is more frequently associated with other psychiatric comorbidity and a family history of mood disorder. Age of Depression Onset One important factor in the etiology and course of depression and cognitive impairment is the age at which an individual experiences his or her first episode of clinically significant depression. Various studies present an age range from years as the lower limit for defining late age of depression onset. 27 Population-based studies suggest that 30% of individuals first experience depression in late life, with 40% first experiencing depression earlier in life and an additional 30% that cannot be reliably determined for a variety of reasons, including difficulty with recall and methodologic issues regarding level of symptomatology sufficient to be classified as a first episode. 28 Late-onset depression is more frequently characterized by medical comorbidity, whereas early-onset depression is more frequently associated with other psychiatric comorbidity and a family history of mood disorder. 27 Apathy occurs more frequently in late-onset depression than early-onset depression. 29 Late-onset depression is associated with pathology of subcortical and deep white matter structures 30 and more frequently occurs with cognitive impairment, typically with prominent features of executive dysfunction that reflect underlying disruption of frontostriatal circuits. 31,32 The etiology of early-onset depression is not as well defined, but research suggests that early-onset depression that is untreated or recurrent is associated with volume loss in the hippocampus 33,34 and possibly contributes to dysfunction of the hypothalamic-pituitary-adrenal-stress axis. 35 In general, individuals who present with first-onset of depression in late life have the higher relative risk of developing some form of dementia. 9 Vascular Depression Community and clinical studies have identified a consistent association between depression and cerebrovascular disease that has led to the vascular depression hypothesis. 30,36,37 Clinically defined vascular depression 37 is characterized by the presence of medical conditions presumed to be associated with cerebrovascular disease and neuropsychological test performances consistent with subcortical dysfunction, specifically in the domains of attention and executive functions. This definition is supported by MRI-based clinical studies that found subcortical ischemic lesions are more common among depressed elders than similarly aged individuals without depression. 38,39 Other MRI studies have demonstrated an association between deepwhite-matter hyperintensities (DWMH) and deficits in memory and executive functions among depressed elders, which was not found among elderly depressed individuals lacking in DWMH and normal controls with or without DWHM. 40 A definition of vascular depression based on ischemic pathology in subcortical gray matter and deep white matter (subcortical ischemic depression, SID) found that 50% of individuals from a communitydwelling tertiary-care sample met this definition of depression. 41 The authors found that SID was characterized by greater age, greater lassitude, and more frequent history of hypertension relative to depressed individuals without SID. This is consistent with associations between cerebrovascular disease and depression in community samples 36 and prospective studies suggesting that vascular pathology appears to be associated with a more persistent and worsening course of depression. 42 These findings suggest that vascular depression is an important clinical entity to characterize as it may result in an acquired and lasting dysfunction in both affect and cognition. MILD COGNITIVE IMPAIRMENT Early detection of cognitive impairment affords the clinician the greatest range of intervention strategies to prevent or forestall a transition to dementia. 43,44 Thus, before focusing on dementia, it is important to first address forms of mild cognitive impairment (MCI), which may represent a transitional stage to dementia for many individuals. While estimates of conversion rates vary, one study found that 35% of individuals with MCI progress to dementia over a 3-year period. 45 Although the essential definition of MCI is the presence of cognitive impairment not meeting criteria for dementia, the diagnostic entity of MCI is heterogeneous 46,47 and for the purposes of this review includes the related conceptualization of cognitive impairment, no dementia (CIND). 48,49 MCI definitions can be broadly classified as amnestic and nonamnestic. Amnestic MCI is characterized by a primary memory disorder with relatively unimpaired or less-impaired function in other neurocognitive domains. 50,51 Nonamnestic MCI, on the other hand, is characterized by impairment in 1 or more neurocognitive domains other than memory, including language, executive function, and visuospatial skills. 52 Whereas most studies indicate that amnestic MCI progresses to Alzheimer disease (AD), 43 nonamnestic MCI is more likely to progress to dementias other than AD. 53 Research now indicates a high rate of cooccurrence between depression and mild cognitive impairment that appears to raise the risk for persistent cognitive impairment and dementia Lippincott Williams & Wilkins 107

4 Potter and Steffens The Neurologist Volume 13, Number 3, May 2007 Depression and Mild Cognitive Impairment One problem with understanding the relationship of depression to MCI is that depression has often been excluded from the definition of this condition. Although this exclusion initially occurred because depression was viewed as a pseudodementia that confounds the detection of true impairment, research now indicates a high rate of co-occurrence between depression and MCI that appears to raise the risk for persistent cognitive impairment and dementia. One study found a 26% cumulative prevalence of depression among individuals with either amnestic or multidomain MCI. 51 Clinical prevalence of amnestic-type MCI was slightly greater than 50% in 2 different studies 54,55 of depressed patients, which is considerably higher than the 3 to 6% prevalence of amnestic MCI among nondepressed individuals. 51,56 Studies including multiple cognitive domains found that 33% 50% of depressed individuals have clinical levels of cognitive impairment. 32,57 Clinical and population-based studies have shown that MCI in depression often persists after depression has remitted. One study of an amnestic MCI definition found that individuals who were classified with this condition at baseline assessment based on neurocognitive performance were approximately 4 times more likely to be classified as amnestic MCI 1 year later while remitted, relative to remitted individuals who were without memory impairment at baseline. 55 Another study found that roughly one third of depressed individuals meeting MCI criteria during their acute depressive episode met MCI criteria 1 year later, despite remission of depressive symptoms. 57 Persistent memory deficits in the context of depression may be an indicator of underlying structural changes that present an elevated risk of converting to AD 12 or another form of dementia. This is supported by previous studies of depressed elders with cognitive impairment not clinically diagnosed as MCI, one of which reported a 43% rate of conversion to AD over a 3-year period 58 and another study reporting an 89% conversion rate to AD over an 8-year span. 59 DEMENTIA Dementia refers to an outcome of changes in the brain that produce dysfunction in memory, thinking, communication, and praxis that impairs an individual s ability to function in daily life. The current classification of dementia based on DSM-IV criteria is (1) impairment in memory and 1 other cognitive domain, (2) insidious onset and progressive decline, (3) exclusion of other etiologies, and (4) interference with everyday social or occupational function. 13 A specific definition of AD established by the National Institute of Neurologic Disorders and Stroke and the Alzheimer disease and Related Disorders Association Working Group (NINDS- ADRDA) 60 differs from DSM-IV in that it (1) does not require memory as one of the impairments, (2) does require formal neuropsychological assessment to objectively characterize cognitive impairment, (3) does not require evidence of social and occupational dysfunction, and (4) does not exclude contributing etiologies such as depression. DSM-based criteria for vascular dementia (VaD) include the broader dementia 108 criteria, as well as (1) evidence of stepwise progression, (2) focal neurologic signs, and (3) evidence to support the presence of cerebrovascular etiology based on physical examination, laboratory results, or medical history. 13 An alternate definition of VaD encompasses dementia secondary to ischemic and hemorrhagic brain lesions and ischemic hypoxia. 61 One autopsy-based study reported that AD is the most prevalent form of dementia (77%), followed by dementia with Lewy bodies (LBD) (26%), VaD (18%), hippocampal sclerosis (13%), and frontotemporal dementia (FTD) (5%). 62 Most of the research on the relationship between depression and dementia is focused on AD and VaD, and these will be presented in greater detail. Up to 75% of individuals diagnosed with Alzheimer disease experience symptoms consistent with depression. Depression in Alzheimer Disease Up to 75% of individuals diagnosed with AD experience symptoms consistent with depression, including mood changes, social withdrawal, apathy, and suicidal ideation 63 ; however, most studies have reported a more consistent range of 30% 50%. 64 Depression in AD is more common among women. 65 Some experts pose a characteristic depressive syndrome in AD, which presents with fewer and less prominent symptoms than major depression. 64,66 Provisional diagnostic criteria for depression in AD emphasize social withdrawal and irritability as particular features of this condition (Table 1). Depression in AD is more common both early in the dementia process and again later when dementia symptoms are most severe, at which time it is often associated with agitation. 67 Other data suggest that approximately half of major depressive episodes precede the onset of dementia but are otherwise equally prevalent across dementia severity when they occur during the course of the disease. 65 Dysthymic disorders, on the other hand, are more likely to occur after AD onset and be more prevalent in milder stages. 65 One important issue in understanding the association between depression and dementia is whether depression is a risk factor for AD or whether it is an early prodrome. Regarding the first issue, one study found that the risk of dementia among members of an AD registry was approximately twice as high when depression preceded AD onset by more than 10 years but that depression less than 10 years before onset was not a significant risk factor. 7 A study conducted in a sample of twins found a contrary result, which was that risk ratios for AD declined as the interval between onset of depression and onset of AD increased. 8 In yet another study, history of depression was not found to be a risk factor for AD in a large population-based sample, regardless of time of onset. 68 Regarding evidence of depression as a prodrome of dementia, one longitudinal, population-based 2007 Lippincott Williams & Wilkins

5 The Neurologist Volume 13, Number 3, May 2007 Contribution of Depression to Cognitive Impairment and Dementia study found that symptoms of depression increased after the onset of dementia but that they did not increase dementia risk. 69 A follow-up study on this longitudinal cohort supported the prodromal nature of depression, finding that it was not associated with cognitive decline over a period of up to 12 years and that decline did not occur without a later diagnosis of dementia, suggesting the presence of an incipient process at the time of decline. 10 Although research has not yet resolved whether depression is more accurately characterized as a risk or prodrome of dementia, the important clinical issue is that the 2 conditions are frequently linked; thus, the presence of depression, particularly of late onset, should raise attention to screening for cognitive impairment as part of a long-term approach to care. Depression in Vascular Dementia Given the strong contribution of cerebrovascular pathology to depression in late life, there should be little surprise that depression is highly prevalent in VaD. Clinical studies have found major depression to be more common in VaD than AD, at approximate prevalence rates of 25% and 10%, respectively, 70,71 and to be more severe. 72 One study found similar 1-year incidence rates for VaD and AD (40% major minor depression), but VaD patients maintained their depressive episodes significantly longer than AD patients, which ultimately resulted in a higher prevalence rate. 73 These clinical findings are supported by a large community study of older adults (Cache County Study on Memory in Aging), which found that depression as rated on the Neuropsychiatric Inventory was significantly higher in VaD than in AD. 74 Depressive symptoms of psychomotor retardation and decreased concentration/attention present diagnostic challenges because they have been found to be predictive of both depression and VaD in a group of stroke patients, and the symptoms of vegetative behaviors, insomnia, and poor appetite were found to be common in VaD regardless of the presence of depression. 75 The similar neuroanatomic pathologies of vascular depression and VaD have led some researchers to speculate that cognitive impairment in late-onset depression may be the same entity as VaD. 76 Depression and Other Dementias Review of other dementing conditions reveals the consistent trend that depression is frequently comorbid with neurologic conditions that affect cognition. For instance, depression prevalence in dementia with LBD is estimated at 20% 65% Data from autopsy studies on the association between depression and presence of LBD found that individuals with late-life depression who developed dementia were most prominent for AD pathology but that LBD and cerebrovascular pathology were present in all cases, which suggests that these pathologies may contribute to late-life depression and cognitive impairment in dementia. 80 Another autopsy study, however, found that depressive symptoms in LBD were not related to severity of LBD pathology and that presence of depression was not useful in distinguishing this disease from AD. 81 Review of depression in frontotemporal dementia (FTD) reveals substantial overlap in neuroanatomic correlates and cognitive profiles, 82 but there is a lack of data for their comorbid prevalence. One review of neuropsychological performance found that the magnitude of deficits in neuropsychological domains was similar in depression and FTD but that individuals with FTD were significantly more impaired in verbal fluency and memory of factual information (semantic memory). 82 Dementia with hippocampal sclerosis (HSD) is commonly viewed as a variant of FTD, 83,84 but it is notable that 63% of individuals with HSD in one study had depression or depressive symptoms. 85 Depression in the context of Parkinson disease (PD) is estimated to be present in up to 50% of this population. 86 Depression in PD is associated with cognitive impairment, as well as increased disability, earlier onset, and more rapid decline in motor symptoms. 86,87 Finally, Huntington chorea, while less common among dementias, is estimated to present with psychiatric symptoms before detectable neurologic symptoms in up to 50% of patients. 88 Depression is the most common psychiatric condition in HD 89 and appears to be associated with striatal pathology. 90 Impairment of activities of daily living is likely an underappreciated feature of depression and one that has important effects on dementia outcomes. Dementia, Depression, and Functional Disability Deficits in activities ADL, particularly by informant report, have been shown to predict individuals who progress from MCI to AD. 91 ADL deficits have also been shown to predict more rapid disease progression and mortality among demented individuals. 92 Impairment of ADLs is likely an underappreciated feature of depression and one that has important effects on dementia outcomes. One study found that among individuals with very early dementia, the presence of depression tripled the risk for functional disability. 93 Other studies reported that the presence of depression in dementia was significantly associated with increased functional impairment and higher utilization of nursing home care 94 and was an independent predictor of nursing home admission 1 year later. 95 In these latter 2 studies, only 30% 35% of depressed individuals were receiving adequate treatment of their symptoms, which suggests that poor detection of depression in conditions of cognitive impairment may lead to worse functional outcomes. Apathy, in particular, appears to be associated with such functional impairments. 96,97 Importantly, functional impairment may also be a marker for adverse cognitive outcomes. Among depressed individuals, self-reported impairments in instrumental activities of daily living (IADL) are associated with more pervasive cognitive impairment 96 and persistence of impairment after depression remits. 55 Another study reported that decline in ADLs rather than cognition precedes the onset of depression among individuals with probable AD. 98 Thus, evidence 2007 Lippincott Williams & Wilkins 109

6 Potter and Steffens The Neurologist Volume 13, Number 3, May 2007 TABLE 2. Clinical Presentations of Major Depressive Episode 13 (MDE) Versus Alzheimer s Disease (AD) Feature MDE AD Diagnosis Often meet MDE criteria Symptoms often less than MDE Age of onset Above or below age 60 Uncommon below age 60 Rate of onset Typically acute Insidious Course Fluctuations, often mood congruent Progressive decline Memory complaints Usually present Variable Affect Depressed Depressed or euthymic Sleep-wake cycle Often disturbed Variable Aphasia/apraxia/agnosia Uncommon Manifest with disease progression Memory Better than self-assessment Worse than self-assessment Improves with retrieval cues Cueing does not help performance Intrusion of previously learned information atypical Intrusion of previously learned information in attempted recall of new material Executive dysfunction Typical Variable, occurs later Processing speed Slowed Normal Effort Decreases with cognitive demand; disproportionate impairment on effortful cognitive tasks; do not know responses Usually normal of functional impairments among individuals with depression may be a warning sign of individuals who are at risk for cognitive decline and that this risk will be lowered by effective identification and treatment of depression. CLINICAL ASSESSMENT Differential Diagnosis of Depression and Dementia One of the challenging issues of clinical diagnosis is distinguishing individuals with depression in the context of early dementia from individuals who are reporting cognitive complaints as part of their depressive episode. The diagnostic challenge is that there is a great deal of symptom overlap between depression and early dementia. For instance, the symptom constellation of decreased concentration and processing speed, irritability, sleep loss, fatigue, and anhedonia that occur in depression can appear similar to the constellation of memory loss, agitation, sleep-wake disturbance, and apathy that often occur together in dementia. Despite similarities between depression and dementia, careful attention to clinical history and presentation help distinguish the 2 conditions (see Table 3). Clinical History The typical clinical course of depression with and without cognitive impairment is often distinct from that of AD and can be delineated along features such as age of onset, rate of change, and general presentation (Table 2). Based on age of onset alone, diagnosis of AD is rare before age Consistent with the underlying nature of AD pathology, the typical course of cognitive change in AD is frequently described as insidious, reflecting a gradual progression of difficulties that evolve from subtle to overt over the course of months to years. In many cases, individuals with early dementia who present for memory evaluations are there at the behest of family members, who often report greater concern than the patient. Although insight into deficits varies across 110 TABLE 3. Components of Extended Evaluation of Depression Clinical and laboratory assessment 1. History of episodes, possible untreated episodes, prior response to treatment, if applicable 2. Specific questions about suicidal ideation and intent; history of suicide attempt 3. Family history of depression and age of onset 4. Performance of daily activities, focus on changes in performance or involvement 5. Comorbid or contributing medical conditions (eg, hypothyroidism, chronic pain) 6. Routine laboratory tests to exclude medical contributors (CBC, TSH, B12/folate) 7. Comprehensive history of vascular risk factors 8. Brain MRI (preferred) or CT, particularly in the context of cognitive impairment, focal neurologic findings, and/or significant vascular risk factors 9. Review medications for possible contributors (eg, -interferon, -blockers) Psychosocial assessment 1. Current stressors, or other factors that could precipitate a reactive mood change, eg, recent losses of family or friends, serious illness to self or loved one, marital discord, work or financial difficulties 2. Positive vs. negative family/social support 3. Community involvement; current level and recent changes individuals with AD, even those who endorse memory complaints tend to underestimate the extent and severity of their deficits. In contrast to individuals with AD, depressed individuals can present with cognitive complaints in either earlyor late-onset depression. Cognitive symptoms have typically developed over the course of weeks to months and usually coincide with mood changes. Depressed individuals frequently refer themselves for memory evaluation, 100 and their level of cognitive complaints is typically greater than performance on objective testing would suggest. Although de Lippincott Williams & Wilkins

7 The Neurologist Volume 13, Number 3, May 2007 Contribution of Depression to Cognitive Impairment and Dementia pressed individuals tend to report more frequent and profound cognitive complaints than individuals with dementia, memory complaints have been found to be predictive of dementia, which suggests that they may be a sign of impairment among some individuals before subtle cognitive changes can be detected. 101 We suggest that memory complaints be considered in relation to objective performance, mood state, and collateral information from friends or family members. Clinical Presentation Like clinical history, certain features of clinical presentation can help differentiate depression from dementia. Foremost, individuals who are primarily depressed are more likely than individuals who are primarily demented to meet criteria for a major depressive episode. 66 As mentioned previously, depressed individuals more frequently self-refer for evaluation than individuals with dementia, and in our clinical experience they are much more likely to arrive at an evaluation without an accompanying family member. Behavioral observation and informal assessment of depressed individuals are often positive for more generalized slowing in thinking and motor function. Depressed individuals may demonstrate reduced effort in responding to detailed or challenging questions in both cognitive testing and interview, often taking the form of a do not know response. Memory may appear compromised, but depressed individuals can often arrive at correct responses with additional thinking time or mnemonic cues that help reduce the cognitive effort required. Individuals with AD are prominent for memory dysfunction, which often does not benefit from additional response time or cueing. Individuals with dementia demonstrate deficits in incidental memory, or information learned without specific intent, which produces errors in temporal orientation that discriminate these individuals from those with primary depression. 102 Cognitive and psychomotor slowing are not prominent among individuals with early to mild AD, but they do demonstrate aphasia, apraxia, and agnosia as their dementia progresses and which are atypical of cognitive impairment secondary to depression. 103 Features of clinical presentation reflecting depression and cognitive impairment can be characterized and quantified by formal screening questionnaires, as discussed below. Screening questionnaires do not diagnose depression but rather characterize the nature and extent of symptoms that are associated with depression. Depression Screening The purpose of depression screening is to identify individuals who may require comprehensive evaluation and treatment of their symptoms. Screening questionnaires do not diagnose depression but rather characterize the nature and extent of symptoms that are associated with depression. Screening measures also do not address the clinical course and duration of a depressive episode, estimate functional impairment, or consider medical and psychiatric comorbidities. Within these limitations, there are several instruments that are useful for identifying symptoms consistent with depression. The Geriatric Depression Scale, for instance, was developed and validated specifically for use with older adults (see Appendix A). 104,105 It avoids somatic and sexual symptoms, evaluates subjective experience of cognitive impairment, and uses a simple yes/no response format that decreases cognitive burden. There are 15- and 30-item versions of the GDS, with sensitivities of 80% 100%; the 15-item version takes 5 10 minutes to complete and is satisfactory for most screening purposes. 106,107 Another widely used instrument is the Center for Epidemiological Studies Depression Scale (CES-D), 108 which is composed of 20 items in a multiple-choice format that take approximately 5 10 minutes to complete. Previous studies have noted confusion among depressed elders with the multiple-choice format, 109 which led to a 10-item modified version with a dichotomous response scale. 110 The modified version appears to have comparable sensitivity and specificity to the full version. The Beck Depression Inventory (BDI-II) 111 is a widely used self-report questionnaire that was not developed specifically for older adults but which may be useful because item content was developed to conform to DSM-IV diagnostic criteria for depression. The approach to screening for depression may change when significant cognitive impairment is present. For instance, validity of self-report questionnaires is poor when there is significant cognitive impairment (eg, Mini-Mental State Examination MMSE 15). 112 The Cornell Scale for Depression in Dementia was designed for use in dementia and specifically includes caregivers in the evaluation. 113 Clinician-based instruments, such as the Hamilton Depression Rating Scale 114 and Montgomery-Asberg Depression Rating Scale, 115 are suitable for use with cognitively impaired individuals, but these require training to achieve acceptable reliability for administration and scoring. Neurocognitive Screening As with screening tools for mood, brief neurocognitive screening measures for dementia have both utility and limitations. The MMSE 116 is the most widely used screening test for neurocognitive function and was originally developed for the dual purpose of estimating the severity of cognitive impairment and providing serial estimates of cognitive change with minimal time expenditure (5 10 minutes). 117 Psychometric studies of the MMSE indicate that it fulfills its original intent, demonstrating sensitivity to moderate to severe cognitive impairment, but that it is less sensitive to milder impairment. 118 The lack of sensitivity to subtle cognitive impairment is attributable to its low ceiling of difficulty, narrow range of cognitive abilities assessed, and differential sensitivity to age, education, and ethnicity. Validity is reduced in psychiatric samples, 119 and detection of right hemisphere dysfunction is poor due to heavy emphasis on verbal tasks. 120 In addition, language items have been deemed too easy to effectively identify mild language defi Lippincott Williams & Wilkins 111

8 Potter and Steffens The Neurologist Volume 13, Number 3, May 2007 cits. 118 Alternatives to the MMSE include the 3MS, 121 which is a modified version of the MMSE that includes 4 additional test items (similarities, birth date and birthplace, animal naming, additional delayed recall) and a broader scoring range. As a modification of the MMSE, an MMSE total score can be derived from a completed 3MS, and it takes no more than a few additional minutes to administer and score. The 3MS performs better than the MMSE in detecting dementia, based more on the expanded scoring than the additional items; however, detection of mild impairment was modest. 122 Another alternative to the MMSE is the 7-Minute Screen (7MS), 123 which combines tasks that are sensitive to the cognitive impairments associated with AD: temporal orientation, cued recall, verbal fluency, and clock drawing. The 7MS can actually take up to 15 or more minutes to administer but was found to be better than the MMSE at detecting both AD and a combined group of other dementia diagnoses. 124 In this study, however, specificity for depression and other psychiatric conditions was poor among nondemented individuals and was worse than the MMSE in this regard. The findings reviewed above are consistent with a comprehensive review of screening for MCI that concluded that current screening measures are insufficient to distinguish individuals with and without clinically significant cognitive impairment, including individuals with depression. 47 Thus, while detection of cognitive impairment with screening measures is reason to consider referring the patient for a comprehensive evaluation of neuropsychological function, which can detect subtle cognitive changes and can aid in differential diagnosis of depression and subtypes of dementia (see below), individuals who pass screening tests, particularly those who are highly educated, may not be free of subtle cognitive impairment. Reasons to refer these individuals for neuropsychological assessment include cognitive deficits reported by patient or informant, evidence of compromised daily activities, significant cerebrovascular risk factors, and family history of dementia. 112 Collateral Information As individuals develop cognitive impairment, deficits in insight, memory, and verbal expression may make it difficult for them to provide reliable self-report on either questionnaires or clinical interview. For instance, the lower reported prevalence of depression in severe AD may be due to the difficulty of assessing depression in the context of profound cognitive impairment. 66 Although we encourage physicians to interview friends or family members who accompany a patient to his or her evaluation, several questionnaires exist that can help informants more objectively report on a range of symptoms that are relevant to dementia. One useful instrument is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). 125 The IQCODE has a 16-question short form that is in the public domain (Appendix A) and provides a cutoff score for the presence of dementia. There is also a formula for using the MMSE and IQCODE together to predict likelihood of dementia (Appendix A). In addition to the IQCODE score itself, it is useful to review the specific areas of decline noted by the informant. Neuropsychiatric features can be screened with the Neuropsychiatric Inventory, 126 which includes ratings for depression/dysphoria, apathy/indifference, sleep disturbance, and appetite disturbance that may be relevant to depression. As mentioned previously, the Cornell Rating Scale for Depression in Dementia considers caregiver report. Informants can also provide valuable information about functional activities, which can be efficiently screened with an instrument such as the Functional Activities Questionnaire. 127 One study found that the disparity between informant and self-report of functional status at baseline, with the informant reporting more impairment than the subject, showed high sensitivity and specificity for conversion of MCI to AD over a 2-year period. 91 The caveat to using informant report to assess a patient s cognitive, emotional, and instrumental functioning is that caregiver reports can be influenced by factors such as their own depression, stress level, and cognitive deficits. For instance, caregivers tend to overestimate symptoms of depression, 128 which suggests that both patient and collateral information are important in obtaining an accurate evaluation of a patient s depression, cognition, and functional ability. Comprehensive Evaluation of Depression and Cognitive Impairment Depression Detection of depression by brief assessment should be followed up with an in-depth evaluation (Table 3). This level of clinical evaluation includes gathering information about comorbid medical illnesses that may contribute primarily or secondarily to depression, medications that may affect cognition, recent social stressors, changes in the patient s interpersonal relationships, and deaths or illnesses among loved ones. Because many individuals with mild to moderate dementia frequently continue to maintain social activities, a recent decline in social participation may reflect social withdrawal or apathy associated with depression, rather than a cognitive deficit. It is also important to specifically broach the issue of suicidality, asking about thoughts, intentions, and any potential plan. Cognitive Impairment There are several clinical situations in which a comprehensive neuropsychological evaluation would be informative to diagnosis and treatment planning. A neuropsychological evaluation provides objective assessment of cognitive function in both breadth and depth, based on standardized tests and procedures and which include (1) memory, (2) fluid and crystallized intellect, (3) attention and concentration, (4) information processing speed, (5) temporal orientation, (6) visuoperceptual processes, (7) language abilities, (8) problem-solving, (9) praxis, and (10) sensory-motor functions. When there is a positive screen for cognitive impairment, neuropsychological testing can be helpful in characterizing the level of impairment across cognitive domains and provide a more detailed assessment within a specific domain of impairment. For instance, an in-depth assessment of memory 2007 Lippincott Williams & Wilkins

9 The Neurologist Volume 13, Number 3, May 2007 Contribution of Depression to Cognitive Impairment and Dementia processes examines specific substrates of memory, such as acquisition, storage, and retrieval, which can help distinguish the hippocampally mediated storage deficits that characterize AD from the more frontally mediated retrieval deficits that characterize a cognitive syndrome of depression. 129 Similarly, neuropsychological evaluation can also provide the detailed assessment of executive/frontostriatal dysfunctions that are characteristic of depression and VaD but which may be inadequately assessed by cognitive screening instruments. 129 Neuropsychological evaluation is also important in cases where patient or family reports indicate cognitive dysfunction but which may be mild enough not to be detected by screening instruments. Such is the case with very early dementia or MCI and where a high level of premorbid intellect would place an individual at the functional ceiling of some screening tests. One important characteristic of neuropsychological assessment is that test scores are referenced to patient age, education, sex, and ethnicity, which helps minimize over- or underdiagnosis of impairment due to bias associated with demographic characteristics. Neuropsychological evaluation is also particularly useful for serial assessment of MCI when it is difficult to estimate whether the trajectory of deficits may be (1) stable (as in stroke), (2) partially to fully reversible (as in depression and some medical conditions), or (3) progressive (as in AD). TREATMENT APPROACHES Pharmacological Treatment of Depression Pharmacological treatment of depression in patients with cognitive impairment is similar to the treatment approach for older adults in general. Specific considerations in treating geriatric depression and other neuropsychiatric symptoms include comorbid medical issues, potential drug interactions, possible side effects, and drug costs (see Herrmann 130 for review). Few studies have been performed directly targeting depression in patients with coexisting cognitive impairment. The Depression in Alzheimer disease Study (DIADS) reported that sertraline was more efficacious than placebo in reducing symptoms of major depression in those outpatients with probable AD. 66,67,131 Patients in the treatment group were also noted to have fewer functional declines and fewer episodes of behavioral disturbance over time. Previous studies finding equivocal results had varying definitions of depression, dementia, and treatment response and limited use of the newest antidepressant medications. 132 Although further research remains to be conducted, current data suggest that older adults with cognitive impairment and depression can be successfully treated with antidepressants. Pharmacological treatment of depression in patients with cognitive impairment is similar to the treatment approach for older adults in general. Cognitive Impairment and Response to Antidepressants Given the many functional disabilities that are exacerbated by comorbid cognitive impairment and depression, it should come as no surprise that cognitive impairment is associated with a poor response to antidepressant therapies. Several studies have shown that indicators of executive dysfunction, such as perseveration and diminished inhibition, are associated with lower remission rates following pharmacologic treatment. 23,133 At least 1 study also found such deficits to predict higher rates of depression recurrence over a 2-year follow-up period 24 ; however, another study did not find executive functions to be related to relapse or recurrence of depression. 134 This latter finding suggests that mood and executive functions may be relatively independent among some depressed individuals, while in others the co-occurrence of executive dysfunction and persistent depression may reflect a common neural substrate, which is likely to involve frontal-subcortical circuitry. The implication of these studies for the clinician treating depression comorbid with cognitive impairment is that these individuals are at higher risk for poor treatment outcome and may require a proactive treatment plan, with frequent monitoring of symptoms, attention to functional disabilities, and augmentation with psychotherapy and/or support groups. Cognitive impairment is associated with a poor response to antidepressant therapies. Nonpharmacologic Approaches to Depression and Cognitive Impairment Although antidepressant medication is an important approach to treating depression in dementia, not all individuals respond to pharmacologic therapy, and some may experience adverse effects. 135 One useful approach in the context of cognitive impairment is to apply interventions that compensate for the compromised abilities. For instance, one 12-week trial of problem-solving therapy was associated with better remission and less disability among depressed elders with executive dysfunction compared with individuals treated with supportive therapy. 136 The authors argued that a key element of their treatment effect was that it offered alternative strategies to individuals who tend to perseverate on maladaptive depressive behaviors due to compromised prefrontal function. Similar approaches to cognitive-behavioral therapy and support groups have been helpful in facilitating problem solving and reducing negative affect among individuals with early dementia. 137 Therapeutic approaches that rely on memory, insight, and problem solving become less tenable as individuals progress in their dementia, yet these more impaired individuals still experience depression and often have caregivers functioning under the burden of stress. Behavioral interventions oriented toward the caregiver rather than the 2007 Lippincott Williams & Wilkins 113

10 Potter and Steffens The Neurologist Volume 13, Number 3, May 2007 TABLE 4. Behavioral Strategies for Decreasing Depression Accompanied by Cognitive Impairment 1. Increase daily enjoyable activities by encouraging activities based on previous interests Modify previous interests to current level of ability: e.g., attend garden shows versus active gardening e.g., decrease duration and intensity of physical activity; walk with partner 2. Initiate activities if patient is unable; arrange rides and company to avoid social isolation 3. Modify or eliminate activities that cause frustration due to impairment e.g., arrange help with finances or household repairs 4. Use redirection to maintain focus on positive experiences and memories Maintain and view photo albums/home movies, encourage discussion of favorite memories Initiate pleasant activity, following strategies 1 3 above 5. Caregivers must monitor and nourish own state of well-being for best response to challenging behavior from patient e.g., respite care, daytime care programs, caregiver support groups patient have proven effective in altering the patterns of day-to-day life that may precipitate and maintain reactive symptoms of depression. Typically, intervention focuses on (1) implementing behaviors and activities that are incongruent with depression, namely, increasing daily pleasant events; and (2) changing patient-caregiver interactions that cause or sustain negative affect. 138 In a study that applied these principles to a controlled treatment trial, 139 AD patients with depression were assigned to 2 active interventions involving either pleasant events or caregiver problem solving, or to one of 2 control conditions (typical care or wait-list). Individuals in each of the 2 active treatment conditions experienced significant improvement in depression, while there was no treatment effect in the control conditions. Sixty-percent of individuals in active treatment demonstrated clinically significant improvement, as opposed to 20% in the control condition. In addition, an unexpected positive effect of decreased depression was found among caregivers in the active conditions, but not in the control conditions. Both patients and caregiver in the active treatment trials maintained significant improvement in depression over a 6-month period. Key behavioral strategies for altering depressive behaviors are presented in Table 4. CONCLUSIONS The current review reveals that depression is highly prevalent in most dementias. Although the presentation of depression in AD may be less profound than in a major depressive episode, the presence of depression in AD and other dementias raises the risk for adverse outcomes and potential treatment challenges. Apathy and early functional decline may be particularly associated with greater decline and impairment, and future research will hopefully shed additional light on this. While depression in conditions of cognitive impairment may accelerate decline, the presence of cognitive impairment in depression complicates treatment response and may lead to persistent deficits. Screening of depression in cases of cognitive impairment is a vital aspect 114 of geriatric practice. The detection of depression should often suggest a more thorough evaluation and a proactive, multimodal approach to treatment. Appendix A: Sources of Selected Screening Measures Geriatric Depression Scale (GDS): Multiple versions of the GDS can be found at: yesavage/ GDS.html. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): Additional information on administration and scoring of this test can be found at edu.au/iqcode. 7-Minute Screen (7MS): Stimulus materials and scoring procedures for the 7MS can found at: org/cgi/data/352/7/692/dc1/1. Interested individuals may wish to contact the author (Paul R. Solomon) for additional information on the availability of this instrument. REFERENCES 1. Koenig HG, Blazer DG. Epidemiology of geriatric affective disorders. Clin Geriatr Med. 1992;8: Hanninen T, Hallikainen M, Koivisto K, et al. A follow-up study of age-associated memory impairment: neuropsychological predictors of dementia. J Am Geriatr Soc. 1995;43: Kindermann SS, Brown GG. Depression and memory in the elderly: a meta-analysis. J Clin Exp Neuropsychol. 1997;19: Lockwood KA, Alexopoulos GS, Kakuma T, et al. Subtypes of cognitive impairment in depressed older adults. Am J Geriatr Psychiatry. 2000;8: Mehta KM, Yaffe K, Langa KM, et al. 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11 The Neurologist Volume 13, Number 3, May 2007 Contribution of Depression to Cognitive Impairment and Dementia 17. Beats BC, Sahakian BJ, Levy R. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychol Med. 1996;26: Austin MP, Mitchell P, Wilhelm K, et al. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia? Psychol Med. 1999;29: Nebes RD, Butters MA, Mulsant BH, et al. Decreased working memory and processing speed mediate cognitive impairment in geriatric depression. Psychol Med. 2000;30: Veiel HOF. A preliminary profile of neuropsychological deficits associated with major depression. J Clin Exp Neuropsychol. 1997;19: Zakzanis KK, Leach L, Kaplan E. On the nature and pattern of neurocognitive function in major depressive disorder. Neuropsychiatr Neuropsychol Behav Neurol. 1998;3: Feil D, Razani J, Boone K, et al. Apathy and cognitive performance in older adults with depression. 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12 Potter and Steffens The Neurologist Volume 13, Number 3, May Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer s disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol. 2002;156: 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: Reichman WE, Coyne AC. Depressive symptoms in Alzheimer s disease and multi-infarct dementia. J Geriatr Psychiatry Neurol. 1995; 8: Ballard C, Neill D, O Brien J, et al. Anxiety, depression and psychosis in vascular dementia: prevalence and associations. J Affect Disord. 2000;59: Sultzer DL, Levin HS, Mahler ME, et al. A comparison of psychiatric symptoms in vascular dementia and Alzheimer s disease. Am J Psychiatry. 1993;150: Ballard CG, Patel A, Solis M, et al. A one-year follow-up study of depression in dementia sufferers. 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