Vascular Disease, Depression, and Dementia

The coexistence of depression with cognitive impairment (CI) in late life has been a source for hypothesis development on the mechanisms underlying mood and cognitive syndromes. An early hypothesis postulated that depression with first onset in late life is a heterogeneous syndrome that encompasses patients whose depression is caused by neurological disorders that may or may not be clinically evident when the depression first appears. This hypothesis was supported by findings suggesting that patients with late-onset depression have more cognitive and neuroradiological abnormalities, greater disability, lower familial prevalence of mood disorders, and less personality dysfunction than elderly people with early-onset depression.1 However, some studies failed to identify differences between late- and early-onset depression, perhaps because of the heterogeneity in both syndromes. Indeed, early-onset depression does not protect patients from developing brain abnormalities similar to those of late-onset depression. If anything, early-onset depression may predispose to such abnormalities. Although research on the late-onset hypothesis did not identify the exact mechanisms of depressive and cognitive symptoms, it yielded findings suggesting that related neurobiological processes contribute to depressive and cognitive symptoms. Late-onset depression was initially viewed as a condition caused by progressive or static neurological disorders, but basic research led to the realization that neurobiological changes occurring during depressive states may interfere with neurogenesis and contribute to neuronal changes that promote depression and CI. Such processes are operative in late- and early-onset depression. Therefore, the path to geriatric depression in most patients may involve an interaction between the pathophysiological changes of depression and neurological changes initiated through other mechanisms. The vascular depression hypothesis exemplifies these interactions. The vascular depression hypothesis postulates that cerebrovascular disease predisposes, precipitates, or perpetuates a depressive syndrome in some elderly patients.1, 2 Vascular depression encompasses depressive syndromes with diverse vascular impairments. Because the definition of vascular depression is still evolving, the vascular depression hypothesis cannot be directly tested, but it has provided the conceptual background for studies of the role of cerebrovascular disease in the development of depressive and cognitive symptoms. In this issue of the Journal of the American Geriatrics Society, the paper by Fuhrer and her colleagues of the PAQUID Study documented that depressive symptoms increase the risk of developing dementia during an 8-year follow-up period,3 but this effect was noted only in men. Moreover, the risk for dementia was 50% higher in depressed hypertensive men than in nonhypertensive men. Hypertension did not increase the risk for dementia in women. Finally, elders who developed vascular dementia had more depressive symptoms than persons without dementia or with Alzheimer's disease (AD). These findings suggest that, in some men, vascular disease leads to depressive symptoms, and a subgroup of those who develop depression progress into dementia. The path from vascular disease to depression to dementia may not be direct and sequential (Figure 1). Vascular disease and depression have a reciprocal relationship. There is evidence that vascular disease promotes development of depression. Patients with hypertension, coronary artery disease, myocardial infarction (MI), and vascular dementia often have high prevalence of depression.4 One in five patients has major depression at the time of diagnostic cardiac catheterization5 or after acute MI.6 Another one in five has minor depression at these times. Approximately one in three patients develops major depression at some time during the 12 months after an MI.7 Depression is a common complication of stroke. Stroke with neurological signs occurs in a small number of older people with depression, but silent stroke without neurological signs is common in elderly depressed populations. Silent stroke was documented in approximately 25% of older depressed Caucasian patients8 and in 80% of Japanese patients.9 Pathways to dementing disorders. Although vascular disease increases the risk of depression, the opposite sequence is also true (i.e., depression may increase the risk for vascular diseases). Approximately 50% of patients with coronary heart disease and major depression have had one or more prior episodes of major depression.6 Depression exacerbates vascular morbidity and increases mortality from vascular diseases.7 Depression may contribute to development of vascular dementia and perhaps to dementias of other etiologies. Depressive symptoms occurring long before the onset of dementia increase the likelihood for later development of AD.10 Moreover, longitudinal studies of community-residing elders have documented that depressive symptoms often precede development of dementia.10 Therefore, depression may be both a risk factor and a prodromal symptom of dementing disorders. The mechanisms by which depression may promote the development of vascular and nonvascular dementia are not well understood, but several observations suggest that biological changes occurring during depression lead to brain impairment. Volume reduction has been reported in the subgenual prefrontal cortex and several regions of the orbitofrontal and dorsolateral cortex of depressed patients.11 Reduced hippocampal volume has been documented in depressed men.12 Hippocampal volume reduction is correlated with the life-time duration of depression in women, although some disagreement exists.11 Excessive secretion of glucocorticoids and other stress-related hormones reduce neurotrophic factors, inhibit neurogenesis, and may increase vulnerability to vascular changes and to amyloid deposits, accelerating the onset of vascular dementia, AD, or mixed dementia. Although the biological abnormalities of depression can increase the risk and progression of dementia, the converse may also be true (i.e., vascular disease damages structures that mediate the development of depression).1, 2, 4 Therefore, even in patients without history of mood disorders, once depression develops as part of vascular brain changes, it may further accelerate the progression of vascular and Alzheimer's neuropathological changes. If indeed vascular disease causes cognitive and depressive symptoms, the question emerges: What are the neural pathways that, when damaged by vascular disease, produce cognitive dysfunction and depressive symptoms? In this issue of the Journal, the paper by Geroldi et al. of the InCHIANTI Study demonstrates that hypertension, atrial fibrillation or electrocardiographic changes, and low high-density lipoprotein cholesterol are associated with cogwheel rigidity, a small step gait, and dysexecutive features.13 These findings are consistent with pathology of the striatum and its connections to the anterior cingulate, prefrontal, and limbic structures. Although this study did not focus on depressive symptoms,13 there is evidence that symptoms and signs reflecting frontostriatal impairment characterize depression in patients with vascular risk factors. Compromised integrity of frontostriatal neural systems and their limbic and hippocampal connections appears to be a central abnormality. The clinical presentation of vascular depression supports this view; most such patients have psychomotor retardation, apathy, and executive dysfunction,2, 14 symptoms characteristic of frontostriatal dysfunction. Structural and functional neuroimaging findings further implicate frontostriatal impairment in vascular depression syndromes. Stroke of the caudate head often leads to depression. In community-residing elders, depressive symptoms were found to be associated with small basal ganglia lesions.15 Most depressed patients with silent cerebral infarction have lesions at the perforating arteries territory, which supply the basal ganglia and their frontal connections.4 More than 40% of depressed elderly patients have lesions of the thalamus and basal ganglia, whereas only 5% of normal elderly controls have such lesions. White matter hyperintensities of older people with depression are most prominent in deep frontal areas. Studies using diverse methods suggest that dysfunction of frontostriatal neural systems and their limbic connections contribute to depression.11, 16 Neuropathological investigations identified abnormalities in neurons and glia in the dorsolateral and the anterior cingulate cortex of depressed individuals. Functional neuroimaging studies conducted at a resting state found that patients with major depression observed abnormal metabolism of the caudate nucleus and frontal regions, including the dorsolateral, orbital-inferior, and medial/anterior cingulate. The metabolism of the amygdala and the orbital cortex is abnormally elevated in patients with unipolar or bipolar major depression. The metabolism of amygdala is positively correlated with severity of depression, whereas orbital metabolism is negatively associated with the severity of depression and with the metabolism of the amygdala. This dysfunction may be related to structural abnormalities of the posterior orbital and anterior cingulate cortex, because morphometric magnetic resonance imaging and histopathological studies of younger adults with familial depressive disorder or bipolar disorder have shown a reduction in glial nerve cells of these structures. Vascular lesions are most common in the perforating artery territory that encompasses the basal ganglia and their frontal and limbic connections and thus may be capable of producing depressive symptoms. The relationships between vascular disease, depression, and dementia suggest that geriatric behavioral syndromes do not have unitary etiology. Understanding these relationships can guide the development of novel prophylactic and therapeutic strategies. Reduction of the overall length of time spent in depression clearly ameliorates suffering, but it is conceivable that it can reduce the risk for dementia later in life. Similarly, antihypertensive therapy and treatment of hyperlipidemia reduce damage of peripheral organs but may also prevent depression and delay the onset and progression of dementing disorders. Therefore, empirical studies in this area have the potential to change clinical practice.