Rishi K. Bhalla, PhD, Meryl A. Butters, PhD

Cognitive functioning in late-life

A growing body of literature suggests a link between depression and cognitive decline.

ABSTRACT: Depression is a highly ate-life depression (LLD) is a of information processing and execu- prevalent psychiatric disorder in heterogeneous disorder that can tive functioning might be particularly older adults. It is associated with Lbe broadly defined as depres- pertinent. Three recent studies report- poor outcomes and comorbidities, sion in individuals age 60 and older. It ed that slowed speed of information including cognitive impairment that is associated with several public processing or working def - can persist following symptomatic health concerns, including increased icits appear to predominantly mediate treatment, and may be a risk factor mortality rates, physical disability, the cognitive impairment associated for in some individuals. functional decline, increased health with LLD.8-10 The literature on cognitive function- care utilization, and increased A further point of interest has ing in late-life depression suggests rate.1-3 Epidemiological data suggest been the difference between recurrent that a remote history of depression that between 11% and 30% of older depression and first-time late-onset and first-time late-onset depression adults experience clinically signifi- de pression. Although both are associ- might both increase the likelihood of cant depressive symptoms.4,5 These ated with cognitive impairment, many persistent cognitive impairment. A rates are higher in clinical settings and studies suggest that late-onset depres- conceptual model based on findings nursing homes.6 Some but not all stud- sion might be disproportionately asso- that depression is associated with ies have found distinctive clinically ciated with executive dysfunction and both chronic elevation of adrenal relevant features associated with attentional deficits7,11,12 rather than the glucocorticoid production and cere- depression that occurs for the first more primary episodic memory defi - brovascular disease may assist in time in late-onset versus earlier-onset, cits seen in early-onset depression.12,13 understanding the heterogeneity in recurrent depression. By contrast, a recent meta-analysis did cognitive outcomes associated with not find increased rates of episodic late-life depression. Because depres- Cognitive functioning memory difficulties in individuals sion can injure and lower in LLD with early-onset versus late-onset brain or cognitive reserve, regular A number of studies have considered depression.7 assessment of cognitive functioning cognitive impairment in late-life de - in older adults with mood disorders pression both qualitatively and quan- Dr Bhalla is a clinical assistant professor in is recommended. titatively. Studies that included a clin- the Department of Psychiatry at the Uni- ical diagnosis of major depression, a versity of British Columbia and the staff comprehensive assessment of cogni- neuropsychologist for the Short Term tion, and a healthy comparison group Assessment and Treatment Centre at Van- have documented deficits in episodic couver General Hospital. Dr Butters is an memory, speed of information pro- associate professor in the Department of cessing, executive functioning, and Psychiatry at the University of Pittsburgh This article has been peer reviewed. visual-spatial ability.7 Deficits in speed School of Medicine.

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The literature to date largely sup- ports the notion that depression is associated with cognitive impairment Depression in some but not all older adults. Speed of information processing and execu- tive functioning appear to be particu- Glucocorticoids Cerebrovascular disease larly important cognitive domains * warranting assessment. Although Hippocampal Generalized Frontostriatal there might be some clinical utility in atrophy ischemia abnormalities distinguishing those with late-onset depression from those with early- onset recurrent depression, it is not Brain/cognitive reserve clear whether this differentiation is related to specific cognitive outcomes. AD causal AD Clinical AD factors pathology LLD as a risk factor for cognitive decline A growing body of literature suggests that depression might increase the risk Figure 1. Proposed predominant mechanisms by which depression increases risk for AD. of cognitive decline and dementia in *The very recently postulated direct pathway leading from hypercortisolemia (elevated glucocorticoids) some older adults following treatment to AD neuropathology is represented with a dashed line because, while evidence is growing, it has at present relatively less support than the other proposed pathways. response or remission of depressive Reproduced from Dialogues in Clinical Neuroscience with the permission of Les Laboratories Servier, symptoms. A recent study found 94% Neuilly-sur-Seine, France.25 of individuals with baseline cognitive impairment remained impaired 1 year depressive symptoms independently and there are likely multiple pathways later despite having achieved remis- predicted a subsequent diagnosis of linking the disorder to persistent cog- sion of their depressive symptoms. MCI 6 years later.20 Longitudinal data nitive decline and dementia. Further, 23% of individuals who were from the Women’s Health and Aging initially classified as cognitively in - Study similarly found that baseline Mechanisms that might tact while depressed were subsequent - depressive symptoms predicted sub- increase risk ly classified as impaired following sequent cognitive decline.21 Other Mechanisms that might increase the resolution of their depressive symp- studies have reported that either a risk depression poses for developing toms.14 In a subsequent study with dif- remote history of depression or a num- AD are described inFigure 1 .25 This ferent participants, 38% of LLD indi- ber of past depressive episodes ap - model is based on findings that LLD viduals were diagnosed with mild pears to in crease the likelihood of later is associated with both chronic eleva- cognitive impairment (MCI) and 10% developing dementia.22 By contrast, tion of adrenal glucocorticoid pro- with dementia following treatment some epidemiological studies have duction and cerebrovascular disease response.15 Other researchers have not found an association between (CVD). Together, these factors may similarly noted that cognitive impair- depression in late life and subsequent lead to hippocampal atrophy and ment persists following treatment development of dementia.23,24 generalized ischemia. Generalized and/or remission of depressive symp- The heterogeneity of cognitive ischemia often has a predilection for toms.16,17 outcomes in LLD makes it challenging frontostriatal regions, leading to ab - Two recent review articles suggest to determine the relationship between normalities that could also serve to that depression in late-life is associated the disorder and an increased risk for maintain or cause subsequent depres- with an ap proximately 50% increased cognitive impairment or future decline sive episodes. These factors can also likelihood of developing dementia in and dementia. A further challenge in - lower brain or cognitive reserve. When general18 and Alzheimer disease (AD) volves determining whether depres- other pre-existing AD casual risk fac- in particular.19 Epidemiological stud- sion itself is a risk factor for or a symp- tors are present, this can hasten the ies have also highlighted this relation- tom of prodromal dementia. Both are progression of underlying AD pathol- ship. One study found that baseline possibilities given the nature of LLD, ogy to clinical manifestation of AD.

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maintaining or increasing brain/ cognitive reserve during aging (e.g., Stable physical and cognitive activity, social Depression Normal cognition Normal cognition 1 over time interaction, healthy diet, decreased stress) will be particularly important for elderly depressed individuals. It is important to note that these healthy Depression-associated behaviors are often the very ones dis- Stable 2 Depression neuropathology MCI Stable MCI continued as a result of depressed (e.g., hippocampal volume loss) over time mood.

Summary Late-life depression is associated with Depression Progression functional decline and a number of 3 MCI AD AD neuropathology (e.g., hippocampal volume loss) over time other poor outcomes, including cog- nitive impairment. Further, impair- ment tends to persist in some individ- uals following symptomatic treatment, and some individuals are at risk for CVD Frontostriatal damage Depression 4 AD progressive cognitive decline. There + Progression + AD neuropathology Hippocampal volume loss MCI over time CVD are likely multiple possible pathways leading to this decline, with the low- ering of brain/cognitive reserve being key. Regular assessment of cognitive functioning in older adults with mood Depression disorders is recommended. CVD Frontostriatal 5 damage Progression MCI Vascular dementia over time Competing interests Dr Butters has received honoraria for reviewing grant applications and speaking Figure 2. Pathways linking depression to five predominant cognitive outcomes. for foundations and nonprofit scientific MCI = mild cognitive impairment; AD = Alzheimer disease; CVD = cerebrovascular disease. organizations. She has grant funding from Reproduced from Dialogues in Clinical Neuroscience with the permission of Les Laboratories Servier, the US National Institutes of Health, which Neuilly-sur-Seine, France.25 has reimbursed her for attending scientific meetings. As a consultant for North Star Brain/cognitive reserve is key in this individual cognitive outcomes shown Neuroscience and Fox Learning Systems, model.26 As depression further injures inFigure 2 .25 she has received remuneration for per- neurons and/or lowers reserve, earlier These possible cognitive outcomes forming neuropsychological assessments. or more frequent (or both) expression include normal congnition, stable MCI, of progressive loss and dementia may AD, mixed AD and CVD, and vascu- References result. The variability in the rate of lar dementia. Mixed AD and CVD 1. Steffens DC, Otey E, Alexopoulos GS, et expression of cognitive impairment or may be the most common outcome in al. Perspectives on depression, mild cog- dementia might in turn be explained individuals with late-onset depression. nitive impairment, and cognitive decline. by differing individual thresholds of An understanding of these possi- Arch Gen Psychiatry 2006;63:130-138. reserve.25 ble pathways and the association 2. Beekman AT, Penninx BW, Deeg DJ, et Since only a subset of individuals between LLD and cognitive impair- al. The impact of depression on the well- with LLD will go on to develop per- ment is important as newer treatment being, disability and use of services in sistent impairment, AD, or other de - approaches that might slow or prevent older adults: A longitudinal perspective. mentias, a number of potential path- cognitive decline become available. Acta Psychiatr Scand 2002;105:20-27. ways may account for the differing Additionally, recommendations for 3. Bruce ML, Ten Have TR, Reynolds CF III,

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et al. Reducing and 10. Nebes RD, Butters MA, Mulsant BH, et nal association of initiation/perseveration depressive symptoms in depressed al. Decreased working memory and pro- and severity of geriatric depression. Am older primary care patients: A random- cessing speed mediate cognitive impair- J Geriatr Psychiatry 2004;12:50-56. ized controlled trial. JAMA 2004;291: ment in geriatric depression. Psychol 18. Jorm AF. History of depression as a risk 1081-1091. Med 2002;30:679-691. factor for dementia: An updated review. Aust N Z J Psychiatry 2001;35:776-781. 19. Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer dis- ease: Systematic review, meta-analysis, and metaregression analysis. Arch Gen Late-life depression is associated with Psychiatry 2006;63:530-538. poor outcomes and comorbidities, including 20. Barnes DE, Alexopoulos GS, Lopez OL, et al. Depressive symptoms, vascular cognitive impairment that can persist following disease, and mild cognitive impairment: symptomatic treatment, and may be a risk Findings from the Cardiovascular Health Study. Arch Gen Psychiatry 2006;63:273- factor for dementia in some individuals. 279. 21. Rosenberg PB, Mielke MM, Xue QL, et al. Depressive symptoms predict inci- dent cognitive impairment in cognitive healthy older women. Am J Geriatr Psy- chiatry 2010;18:204-211. 4. Blazer DG. Depression in late life: Review 11. Murphy CF, Alexopoulos GS. 22. Green RC, Cupples LA, Kurz A, et al. and commentary. J Gerontol A Biol Sci network dysfunction and treatment Depression as a risk for Alzheimer dis- Med Sci 2003;58:249-265. response of geriatric depression. J Clin ease: The MIRAGE study. Arch Neurol 5. Steffens DC, Fisher GG, Langa KM, et al. Exp Neuropsychol 2006;28:96-100. 2003;60:753-759. Prevalence of depression among older 12. Rapp MA, Dahlman K, Sano M, et al. Neu- 23. Lindsay J, Laurin D, Verreault R, et al. Americans: The Aging, Demographics ropsychological differences between Risk factors for Alzheimer’s disease: A and Memory Study. Int Psychogeriatr late-onset and recurrent geriatric major prospective analysis from the Canadian 2009;21:879-888. depression. Am J Psychiatry 2005; Study of Health and Aging. Am J Epi- 6. Waraich P, Goldner EM, Somers JM, et 162:691-698. demiol 2002;156:445-453. al. Prevalence and incidence studies of 13. Salloway S, Malloy P, Kohn R, et al. MRI 24. Ganguli M, Du Y, Dodge HH, et al. mood disorders: A systematic review of and neuropsychological differences in Depressive symptoms and cognitive the literature. Can J Psychiatry 2004; early- and late-life-onset geriatric depres- decline in late life: A prospective epi- 49:124-138. sion. Neurology 1995;46:1567-1574. demiological study. Arch Gen Psychiatry 7. Herrmann LL, Goodwin GM, Ebmeier KP. 14. Bhalla RK, Butters MA, Mulsant BH, et 2006;63:153-160. The cognitive neuropsychology of de- al. Persistence of neuropsychologic 25. Butters MA, Young JB, Lopez O, et al. pression in the elderly. Psychol Med deficits in the remitted state of late-life Pathways linking late-life depression to 2007;37:1693-1702. depression. Am J Geriatr Psychiatry persistent cognitive impairment and de - 8. Butters MA, Whyte EM, Nebes RD, et al. 2006;14:419-427. mentia. Dialogues Clin Neurosci 2008; The nature and determinants of neu- 15. Bhalla RK, Butters MA, Becker JT, et al. 10:345-357. ropsychological functioning in late-life Patterns of mild cognitive impairment 26. Stern Y. What is cognitive reserve? The- depression. Arch Gen Psychiatry 2004; after treatment of depression in the eld- ory and research application of the 61:587-595. erly, Am J Geriatr Psychiatry 2009; reserve concept. J Int Neuropsychol Soc 9. Sheline YI, Barch DM, Garcia K, et al. 17:308-316. 2002;8:448-460. Cognitive function in late life depression: 16. Lee JS, Potter GG, Wagner HR, et al. Per- Relationships to depression severity, sistent mild cognitive impairment in geri- cerebrovascular risk factors and pro- atric depression. Int Psychogeriatr 2007; cessing speed. Biol Psychiatry 2006; 19:125-135. 60:58-65. 17. Murphy CF, Alexopoulos GS. Longitudi-

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