Citation
Vinkers, D. J. (2005, September 15). Atheroslerosis, cognitive impairment, and depression
in old age. Retrieved from https://hdl.handle.net/1887/3386
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Disentangling the relation between atherosclerosis, cognitive impairment, and
depression in old age
Vinkers DJ, van der M ast RC, Stek M L, W estendorp RGJ, Gussekloo J. Disentangling the relation between atherosclerosis, cognitive impairment,
Abstract
Introduction
Both cognitive impairment and depression are highly prevalent in elderly subjects, and account for a large part of the burden of disability and use of healthcare resources in old age1. Moreover, cognitive decline and depression frequently co-occur in old age, while showing substantial overlap in signs and symptoms2 3 4. Therefore, it has even been suggested that atherosclerosis, being a final common pathway, leads to both cognitive impairmant and late-onset depression (figure 9.1)5 6 7. Here, we present a review of our findings in the Leiden 85-plus Study combined with a review of the existing literature about the relationship between atherosclerosis on the one hand and cognitive impairment and late-onset depression on the other hand.
Figure 9.1 Current understanding of the relation between atherosclerosis, cognitive impairment, and late-onset depression. It has been proposed that atherosclerosis is a common causal pathway of cognitive impairment5 and late-onset depression6, explaining their common co-occurrence in old age7.
Atheroscl
erosis and cognitive impairment
The major types of dementia in old age are Alzheimer's disease and vascular dementia8. Clinically, both dementias are characterized by cognitive impairment interfering with daily functioning. Since many years atherosclerosis is regarded as the cause of vascular dementia, while by definition, atherosclerosis does not play a role in Alzheimer's disease9. Etiologically, both dementias may however not be as different as has been proposed in clinical classifications of dementia10.
Atherosclerosis
There is accumulating evidence that atherosclerosis is also involved in the etiology of Alzheimer's disease. First, in post-mortem analyses, the pathological characteristics of Alzheimer's disease are frequently observed in combination with manifestations of atherosclerosis11 12 13 14. Second, indicators of atherosclerosis such as vessel wall thickness and carotid artery plaques are associated with Alzheimer's disease15 16 17, although this has not yet been shown prospectively. Third, well known cardiovascular risk factors including smoking and hypertension and have been related to the development of Alzheimer's disease18 19 20 21
. Indeed, treatment of blood pressure prevents the occurrence of Alzheimer's disease in elderly subjects22 23 24. Furthermore, hypercholesterolemia is associated with an increased incidence of Alzheimer's disease in observational studies25 26. Clinical trails could, however, not confirm that cholesterol lowering therapy protects against cognitive decline27 28 29. Possibly, hypercholesterolemia is treated in healthy subjects only, explaining the difference between observational studies and clinical trials. Fourth, the most important genetic risk factor for the occurrence of Alzheimer disease is the APOE4 gene, which is also linked to atherosclerosis30 31 32 33. Fifth, cerebral white matter hyperintensities, that are assumed to have a vascular ischemic origine34, are frequently observed on magnetic resonance imaging (MRI) scans of subjects with Alzheimer's disease35. Finally, brain infarctions exacerbate the clinical expression of Alzheimer's disease 36 37 38. Thus, there is strong evidence that atherosclerosis is an important causal factor in both vascular dementia and Alzheimer's disease, leading to cognitive impairment in old age39 40 41. Several prospective studies indeed confirmed a longitudinal relation between cumulative measurements of vascular disease and the occurrence of cognitive decline in elderly subjects42 43 44.
Within the population-based Leiden 85-plus Study, we prospectively followed 599 subjects from age 85 years onwards with annual assessments of various cognitive domains. At age 85 years, the burden of atherosclerosis including myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery was assessed by history taking and electrocardiography. Cross-sectionally, atherosclerosis was related to a more impaired global cognitive function, lesser attention, and a slower processing speed45. During five years of follow-up, atherosclerosis was related to an accelerated decline of immediate recall memory and delayed recall memory46. The relation between atherosclerosis and cognitive impairment was unaffected by adjustment for depressive symptoms, a history of stroke, or presence of chronic diseases. Thus, in the oldest old, atherosclerosis contributed independently to cognitive decline.
Atherosclerosis and late-onset depression
There is little direct evidence however for the vascular depression hypothesis. First, although there is a co-occurence of late-onset depression and cardiovascular events51 52 53, it is likely that this co-occurrence reflects the psychological undermining of the inflicted patient. This is supported by the relation between the amout of physical and social disability after the onset of cardiovascular diseases and the subsequent emergence and course of depression54 55 56 57 58 59 60 61
. Approximately half of all depressed subjects improve rapidly after the onset of a cardiovascular disease62. No relationships have been found between well known cardiovascular risk factors as hypertension and hypercholesterolemia and late-onset depression63 64 65 66 67 68, and the treatment of hypertension and hypercholesterolemia does indeed not reduce late-onset depression69 70. Furthermore, various studies showed that the number of vascular diseases and vascular risk factors are not related to late-onset depression71 72 73 74 75
, although not unequivocally76, or a relation which disappeared after adjustment for disability77 78. Second, although late-onset depression is cross-sectionally associated with white matter hyperintensities on magnetic resonance imaging (MRI) scans of the brain79 80 81 82 83 84 85 86
, there is hitherto no evidence that white matter hyperintensities cause late-onset depression prospectively. Furthermore, the association between white matter hyperintensities and late-onset depression disappears after adjustment for functional impairment87 88 89, which may be explained by the relation between white matter hyperintensities and functional disability90 91, gait and balance dysfunction92 93 94, urinary incontinence95 96, and decreased pulmonary function97. Third, white matter hyperintensities in depressed elderly are often located at the level of the dorsolateral prefrontal cortex98 99 100 101, which is biologically related to apathy rather than to depression102 103 104. Apathy, being a distinct clinical entity with different psychopathology, treatment, and prognostic implications, differs from late-onset depression105 106. Fourth, post-mortem analyses show that although there is a relation between late-onset depression and post-ischaemic inflammation, no such relation exists between late-onset depression and atherosclerosis107 108. Fifth, although there is a cross-sectional association between non-invasive measurements of atherosclerosis and late-onset depression, this association may at least partly be explained by functional disability109. Finally, genes which are associated with atherosclerosis, including the APOE4 gene, are not related to late-onset depression110 111 112 113 114. Taken together, there is no evidence that there is a causal relationship between atherosclerosis and late-onset depression. In line, two recent reviews on this topic concluded that, although there are important interactions between atherosclerosis and late-onset depression, the concept of vascular depression may be too restrictive115 116.
Temporal relationship between cognitive impairment and late-onset
depression
Clinical experience and research evidence learns that, in old age, signs and symptoms of cognitive impairment are difficult to distinguish from depression, and that cognitive impairment and depression frequently co-occur2 3 4. The temporal relation between them remains, however, unclear since most studies examined only the relationship of depression with the subsequent development of cognitive impairment117 118 119 120 121 122. Causal inference of these studies is hampered by the possibility that depression may be an early sign instead of an independent risk factor for cognitive impairment. Hitherto, one large population-based study studied the temporal relation between cognitive impairment and depression in elderly subjects. This study found that depression is an early manifestation rather than a predictor of cognitive impairment123. The view that late-onset depression is a concomitant phenomenon of cognitive decline is further supported by the finding that succesful treatment of late-life depression does not lead to significant cognitive improvement124 125 126. Furthermore, neuropathological studies showed that the association between cognitive impairment and depression in elderly subjects could not be explained by a common etiology as cerebral infarctions127, cortical plaques and tangles128, or loss of serotonergic129 and noradrenergic neurons130. These findings make it again less likely that atherosclerosis is a common causal pathway of cognitive impairment and late-onset depression.
Within the Leiden 85-plus Study, we examined the temporal relation between various cognitive domains and depressive symptoms131. Cross-sectionally, cognitive impairment and depressive symptoms were highly significant correlated. Impairment of attention, immediate recall memory, and delayed recall memory at baseline were associated with an accelerated increase of depressive symptoms during follow-up. In contrast, depressive symptoms at baseline were not associated with an accelerated cognitive decline during follow-up. Thus, in the oldest old, cognitive impairment preceded the onset of depressive symptoms and not the other way round.
In conclusion, we presented a summary of our findings within the Leiden 85-plus Study and reviewed the existing literature about the relation between atherosclerosis, cognitive impairment, and late-onset depression. We found strong evidence for a causal relationship between atherosclerosis and cognitive impairment, but not for a causal relationship between atherosclerosis and late-onset depression. Furthermore, it is likely that cognitive impairment contributes to the development of late-onset depression and not the other way round (figure 9.2). Clinical implications of this proposed view are that although depression and cognitive impairment frequently co-occur in old age, the presence of late-onset depression only does not mean that cognitive decline is yet to come. The prevention of atherosclerosis may prevent cognitive impairment in old age, and this, in turn, may forestall late-onset depression.
Figure 9.2 Proposed relation between atherosclerosis, cognitive impairment, and late-onset depression. Atherosclerosis is related to cognitive impairment, but not to late-onset depression46. Cognitive impairment contributes to the development of late-onset depression131.
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