Blowing hot and cold over depression and cognitive impairment

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In clinical practice, one may come across an elderly patient with severe and incapacitating depression. Typically, such a patient is morbidly preoccupied and hardly able to engage with the external world. If a person does not attend to external stimuli, then information is not registered efficiently. If information is not registered efficiently, then recall will be compromised, and impairment in learning and recall constitutes memory impairment in the true sense of the concept. Such a clinical scenario leads to an intuition that late-life depression is associated with cognitive impairment. Indeed, this clinical observation is also supported by cross-sectional clinical1,2 as well as population-based studies.3,4 Additionally, longitudinal studies have demonstrated depression to be a risk factor for incident dementia or mild cognitive impairment (MCI).5-7 These observational findings are supported by plausible neurobiological theories (table e-1 on the Neurology® Web site at www.neurology.org).8

Counting the cross-sectional and longitudinal findings, one is tempted to conclude that the field of aging has taken 2 steps forward in establishing depression as a risk factor for incident dementia or MCI. However, the story does not end there. A number of other studies, including large prospective cohort studies, have reported no association between depression and cognitive impairment.9,10 Therefore, it appears that the field is blowing hot and cold in the same breath. Thus, we are well justified to seek more data to clarify this issue.

The current issue of Neurology® has 3 articles that address the dilemma of the relationship between depression and cognitive impairment.11-13 All the articles have 2 important common denominators: all 3 studies are prospective cohort studies that measured depression by using the same validated instrument (Center for Epidemiologic Studies Depression Scale [CES-D]).14 The prospective designs mean that it is possible to identify the presumed cause of cognitive impairment (i.e., depression) before the appearance of the effect (i.e., incident Alzheimer disease [AD] or MCI). This temporal sequence improves the strength of etiologic inferences. The use of a common measurement tool means all the “blessings and curses” of the instrument are equally applicable to all 3 studies. All 3 studies have thus minimized sampling bias and variability by prospective design and use of identical depression measurement scales, which increases confidence in their findings.

In the first article, Saczynski and colleagues from the Framingham Heart Study11 followed a cohort of 947 cognitively normal elderly (depressed and nondepressed persons) for up to 17 years, to the outcome of incident dementia. They observed that depression (as measured by CES-D ≥16) was associated with an increased risk of dementia and AD. The second study raised the ante by examining the dose-response relationship between the number of depressive episodes and the risk of dementia (table e-1). Dotson et al.12 evaluated 1,239 study participants of the Baltimore Longitudinal Study of Aging.13 One episode of elevated depressive symptoms (CES-D ≥16) conferred an 87% to 92% increased risk of dementia, whereas 2 or more episodes doubled the risk of incident dementia. However, recurrence of depressive symptoms did not increase the risk of incident MCI, suggesting that incident MCI may not necessarily be identical with incident dementia.

In the third study, Wilson and colleagues from the Chicago Health and Aging project15 investigated the change in depressive symptoms before and after the onset of dementia of Alzheimer type (DAT). They followed depressed and nondepressed cognitively normal elderly persons to the outcome of incident AD (n = 357). Subjects completed the self-reported CES-D before the onset of dementia as well as after the onset of mild to moderate dementia (the analysis did not include patients with severe dementia). However, Wilson and colleagues realized that self-reported depressive symptoms may be biased by disease burden; therefore, they conducted a secondary analysis by measuring depression using an informant-based instrument in another sample (n = 340 persons with and without cognitive impairment) derived from the same population. Regardless of how they measured depression (self-report vs informant-based), there was no substantial increase in depressive symptoms before or after the onset of DAT. This finding is consistent with a previous report.15 Wilson and colleagues posit that chronic illness may not necessarily lead to worse mood.

If we agree that there is a real association between depression and dementia/MCI, as these studies suggest, then the next step is to understand the mechanism linking depression with cognitive impairment. As discussed above, none of the 3 studies investigated mechanism of disease linking depression with dementia/MCI; however, they prompt discussion of theories that address mechanism of disease. Currently, there are 4 tenable possibilities.7,16 1) Direct causal hypothesis: severe and repeated major depression may directly cause cognitive impairment via a glucocorticoid (GC) pathway. According to this model, depression leads to excessive secretion of GCs that in turn induce excessive secretion of excitotoxic amino acids; additionally, GC may have adverse effects on neurotrophic factors. These processes may culminate in hippocampal atrophy.8 Depression may also directly cause cognitive impairment in the elderly via the vascular depression hypothesis.17 This theory posits that a combination of late-life depression and cerebrovascular factors (e.g., white matter hyperintensity) may lead to cognitive impairment. If the direct causal hypothesis were true, then treatment of depression may lead to primary prevention of dementia/MCI. However, to date, there are no adequate data to support this mechanism. 2) Reverse causality hypothesis: depression is an emotional response to an evolving cognitive impairment. 3) Confounding hypothesis: AD neurodegenerative pathology causes both the depression and the cognitive impairment. There are 3 criteria that need to be met at the same time in order to clearly identify a confounder: first, to identify the association of interest; second, to establish that the confounder is noncausally or causally associated with the exposure of interest; third, the confounder is causally associated with the outcome of interest. Age is a classic confounder. AD pathology (e.g., plaques and tangles) is another potential confounder (figure).18 4) Interaction hypothesis: there is a synergistic interaction between depression and a biologic factor to lead to incident dementia/MCI.7

The association between late-life depression and cognitive impairment does not appear to be spurious. However, there is insufficient evidence at present to support the hypothesis that depression has a direct causal relationship with subsequent dementia. Only a future mechanism of disease study with a biologic marker for depression can clearly identify which of the 4 hypotheses is most pertinent in explaining the link between depression and dementia/MCI.

REFERENCES

1. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T. The course of geriatric depression with “reversible dementia”: a controlled study. Am J Psychiatry 1993;150:1693–1699.
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2. Butters MA, Whyte EM, Nebes RD, et al. The nature and determinants of neuropsychological functioning in late-life depression. Arch Gen Psychiatry 2004;61:587–595.
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3. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 2002;288:1475–1483.
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4. Geda YE, Roberts RO, Knopman DS, et al. Prevalence of neuropsychiatric symptoms in mild cognitive impairment and normal cognitive aging: population-based study. Arch Gen Psychiatry 2008;65:1193–1198.
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5. Devanand DP, Sano M, Tang MX, et al. Depressed mood and the incidence of Alzheimer's disease in the elderly living in the community. Arch Gen Psychiatry 1996;53:175–182.
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6. Barnes DE, Alexopoulos GS, Lopez OL, Williamson JD, Yaffe K. Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Arch Gen Psychiatry 2006;63:273–279.
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7. 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.
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8. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000;57:925–935.
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9. Becker JT, Chang YF, Lopez OL, et al. Depressed mood is not a risk factor for incident dementia in a community-based cohort. Am J Geriatr Psychiatry 2009;17:653–663.
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11. Saczynski JS, Beiser A, Seshadri S, Auerbach S, Wolf PA, Au R. Depressive symptoms and risk of dementia: the Framingham Heart Study. Neurology 2010;75:35–41.
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12. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology 2010;75:27–34.
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13. Wilson RS, Hoganson GM, Rajan KB, Barnes LL, Mendes de Leon CF, Evans DA. Temporal course of depressive symptoms during the development of Alzheimer disease. Neurology 2010;75:21–26.
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14. Radloff L. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385–401.
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RELATED ARTICLES

>>> R.S. Wilson, G.M. Hoganson, K.B. Rajan, L.L. Barnes, C.F. Mendes de Leon, and D.A. Evans. Temporal course of depressive symptoms during the development of Alzheimer disease. Neurology July 6, 2010 75:21-26.

Objective: To characterize change in depressive symptoms before and after the onset of dementia in Alzheimer disease (AD).

Method: We used data from the Chicago Health and Aging Project, a longitudinal cohort study of risk factors for AD in a geographically defined population of old people. Two subsets were analyzed. In 357 individuals who developed incident AD during the study, self-report of depressive symptoms (Center for Epidemiologic Studies Depression Scale) was obtained at 3-year intervals for a mean of 8 to 9 years. In 340 individuals who agreed to annual data collection, informant report of depressive symptoms (Hamilton Depression Rating Scale) was obtained for a mean of 3 years after a diagnosis of AD (n = 107), mild cognitive impairment (n = 81), or no cognitive impairment (n = 152).

Results: The incident AD group reported a barely perceptible increase in depressive symptoms during 6 to 7 years of observation before the diagnosis (0.04 symptoms per year) and no change during 2 to 3 years of observation after the diagnosis except for a slight decrease in positive affect. In those with annual follow-up, neither AD nor its precursor, mild cognitive impairment, was associated with change in informant report of depressive symptoms during a mean of 3 years of observation.

Conclusion: Depressive symptoms show little change during the development and progression of AD to a moderate level of dementia severity.

http://www.neurology.org/content/75/1/21.full


>>> Vonetta M. Dotson, May A. Beydoun, and Alan B. Zonderman. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment Neurology July 6, 2010 75:27-34.

OBJECTIVE: A history of depression has been linked to an increased dementia risk. This risk may be particularly high in recurrent depression due to repeated brain insult. We investigated whether there is a dose-dependent relationship between the number of episodes of elevated depressive symptoms (EDS) and the risk for mild cognitive impairment (MCI) and dementia.

METHODS: A total of 1,239 older adults from the Baltimore Longitudinal Study of Aging were followed for a median of 24.7 years. Diagnoses of MCI and dementia were made based on prospective data. Participants completed the Center for Epidemiologic Studies Depression Scale at 1- to 2-year intervals and were considered to have an EDS if their score was > or = 16. Kaplan-Meier survival curves, log-rank test for trend for survivor functions, and Cox proportional hazards models were conducted to examine the risk of MCI and dementia by number of EDS.

RESULTS: We observed a monotonic increase in risk for all-cause dementia and Alzheimer disease as a function of the number of EDS. Each episode was associated with a 14% increase in risk for all-cause dementia. Having 1 EDS conferred an 87%-92% increase in dementia risk, while having 2 or more episodes nearly doubled the risk. Recurrence of EDS did not increase the risk of incident MCI.

CONCLUSIONS: Our findings support the hypothesis that depression is a risk factor for dementia and suggest that recurrent depression is particularly pernicious. Preventing the recurrence of depression in older adults may prevent or delay the onset of dementia.

http://www.neurology.org/content/75/1/27.full


>>> J.S. Saczynski, A. Beiser, S. Seshadri, S. Auerbach, P.A. Wolf, and R. Au. Depressive symptoms and risk of dementia: The Framingham Heart Study Neurology July 6, 2010 75:35-41

Objectives: Depression may be associated with an increased risk for dementia, although results from population-based samples have been inconsistent. We examined the association between depressive symptoms and incident dementia over a 17-year follow-up period.

Methods: In 949 Framingham original cohort participants (63.6% women, mean age = 79), depressive symptoms were assessed at baseline (1990-1994) using the 60-point Center for Epidemiologic Studies Depression Scale (CES-D). A cutpoint of ≥16 was used to define depression, which was present in 13.2% of the sample. Cox proportional hazards models adjusting for age, sex, education, homocysteine, and APOE ε4 examined the association between baseline depressive symptoms and the risk of dementia and Alzheimer disease (AD).

Results: During the 17-year follow-up period, 164 participants developed dementia; 136 of these cases were AD. A total of 21.6% of participants who were depressed at baseline developed dementia compared with 16.6% of those who were not depressed. Depressed participants (CES-D ≥16) had more than a 50% increased risk for dementia (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.04-2.84, p = 0.035) and AD (HR 1.76, 95% CI 1.03-3.01, p = 0.039). Results were similar when we included subjects taking antidepressant medications as depressed. For each 10-point increase on the CES-D, there was significant increase in the risk of dementia (HR 1.46, 95% CI 1.18-1.79, p < 0.001) and AD (HR 1.39, 95% CI 1.11-1.75, p = 0.005). Results were similar when we excluded persons with possible mild cognitive impairment.

Conclusions: Depression is associated with an increased risk of dementia and AD in older men and women over 17 years of follow-up.

http://www.neurology.org/content/75/1/35.full