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San Antonio, TX
Dr. Royall is Julia and Van Buren Parr Professor for Alzheimer’s Research in Psychiatry, and Chief, Division of Aging and Geriatric Psychiatry, The University of Texas Health Sciences Center at San Antonio.
Correspondence to: Donald R. Royall, MD, Division of Aging and Geriatric Psychiatry, The University of Texas Health Sciences Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, Mail Code 7792
The psychometric correlates of mortality can be underestimated in a world that values physiologic explanations. Nonetheless, both cognitive impairment and depression are significant predictors of mortality in elderly populations. It is important to note that these risks are often statistically independent of, and additive to, those associated with comorbid physical conditions. This suggests that psychiatric illness itself may increase mortality via direct effects on the CNS.
In this issue of CHEST (see page 1687), Antonelli-Incalzi et al1 report a significant association between performance on a single cognitive measure, the Hécaen copy to landmarks test, and mortality in patients with advanced COPD. This effect was independent of physiologic risks, such as hypoxemia, comparable in size (actually stronger than FEV1!) and additive to the risk of hypoxemia. More than 30% of nonhypoxemic patients who failed this task died over 5 years. Another striking feature is that this effect was limited to the Hécaen copy to landmarks test, and was not seen with the other cognitive measures in their battery.
The data set of Antonelli-Incalzi et al1 does not allow them to test the mechanism(s) by which performance on the Hécaen copy to landmarks test can be associated with mortality. However, drawing tasks have been specifically associated with mortality in a variety of other conditions, including both Alzheimer disease (AD)2 and nondemented elders.3 As in this study, performance on drawing tasks (ie, copying figures and clock drawing, respectively) was uniquely associated with mortality. In the study of Claus et al,2 the Cambridge Cognitive (CAMCOG) assessment battery was significantly related to survival in early AD (p < 0.001). However, its predictive power was based on only two items, copying a spiral and a three-dimensional house. The effect was independent of age, sex, education, dementia severity, total CAMCOG score, and symptom duration. In the study of Lavery et al,3 the risk of mortality in nondemented seniors with clock-drawing impairments was doubled over 3 years, independently of age, depression, Mini-Mental State Examination scores, comorbid medical conditions, number of prescribed medications, and measures of gait and balance.
As in the study by Antonelli-Incalzi et al,1 Lavery et al3 ascribe these risks to impairments in executive function. Executive functions organize other cognitive skills into complex goal-directed activities. Clock drawing can be conceptualized as the interaction between practice skills (visuomotor skills [ie, copying] mediated by the parietal lobes) and their executive control systems (related to the frontal lobes). The CNS substrates of clock drawing are not well described but presumably include regions of interest in both the frontal cortex and the right parietal lobes. The Hécaen copy to landmarks test has itself been associated with lesions to these regions. Moreover, my group has shown that the clock drawing test used in study by Lavery et al3 (ie, CLOX1) is significantly associated with executive function (as measured by the Executive Interview [EXIT25]).45 In contrast, CLOX2, a simple copying task, was not significantly associated with EXIT25 scores independently of CLOX1.6
Antonelli-Incalzi et al1 suggest that the executive impairments of their COPD patients may contribute to mortality by undermining their self-care capacity and medication adherence. This is a reasonable hypothesis. Executive function, particularly as measured by the EXIT25, is a strong predictor of functional outcomes,7 executive impairment is common in medical patients,8 and the EXIT25 has already been shown to be an accurate predictor of the capacity of elderly COPD patients to competently use their inhalers.9 However, the data from my group tend to contradict this hypothesis.1
We have studied the psychometric correlates of mortality over 5 years among 242 septuagenarian retirees. All were nondemented at baseline and lived at noninstitutionalized levels of care within a single retirement community. Previous cross-sectional and longitudinal studies in this cohort have clearly demonstrated that executive measures, including the EXIT25 and CLOX1, but not CLOX2, are significantly associated with functional status and level of care.1011 However, neither is a significant predictor of mortality,12 nor are memory measures, nor are verbal measures. Instead, only nonexecutive nonverbal measures were significantly associated with mortality in multivariate models. CLOX2 predicted mortality independently of CLOX1. It also predicted mortality independently of age, gender, level of care, instrumental activities of daily living, activities of daily living, self-rated health, recent hospitalization, and physician visits. Thus, the association between mortality and this nonverbal measure, presumably reflecting right hemisphere dysfunction outside the frontal lobe, does not appear to be mediated by frailty or physical illness. Thirty-five percent of those who failed CLOX2 had died 5 years later. All were living in independently at baseline.
We have proposed an alternative explanation for the specific association between visuospatial cognition and mortality.13 The CNS lesions that affect practice skills often affect the right insular cortex.14 They also increase mortality.1516 The insula is among the highest levels of autonomic control. In humans, insular autonomic control is lateralized, such that sympathetic function is modulated by the right insula. Asymmetric right insular lesions are associated with unopposed parasympathetic modulation, a condition that is conducive to bradyarrythmias, prolonged QT intervals, syncope, falls, hip fractures, ... and death. In fact, right anterior insular epileptic foci can present with asystole.17
Thus, the specific association between visuospatial cognitive measures and mortality may in fact be mediated by autonomic dysfunction and cardiac arrhythmia. Moreover, these may directly reflect the CNS effects of structural and functional brain disease. The study by Antonelli-Incalzi et al1 demonstrates that the risks associated with right hemisphere dysfunction are comparable to those of physiologic signals. Moreover, they may be additive. Thus, it behooves us to assess and intervene against both the physical and mental ailments of our patients. We ignore either realm at their peril.
Footnotes
Dr. Royall holds copyrights for the Executive Interview (EXIT25) and CLOX: An Executive Clock-Drawing Task.
References
This article has been cited by other articles:
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  P. C. Goldstein, R. Antonelli-Incalzi, C. Pedone, A. Corsonello, and F. Rengo Drawing Impairment Predicts Mortality in Severe COPD: A Naive Approach to COPD Mortality Prediction Chest, October 1, 2007; 132(4): 1411 - 1412. [Full Text] [PDF]
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