Is Sleep Apnea a Cause of Reversible Dementia in Old Age?

Some forms of dementia may be reversible. Although Alzheimer's Disease (AD) is usually thought to constitute the majority of dementia cases, other forms of medical disease (e.g., thyroid, renal, or hepatic conditions, B12 or folate deficiency) may also induce dementia.1,2 Despite this recognition of other forms of dementia, the actual prevalence of such conditions has often been questioned, with relatively few cases noted to be truly reversible. For example, Clarfield's review3 of previous studies encompassing 2889 dementia cases noted that prevalence of such dementias is only about 3%. In contrast to such relatively uncommon metabolic or nutritional causes of dementia, cognitive impairment related to cardiovascular disease may be far more prevalent and, perhaps, more likely amenable to prevention. An impressive array of epidemiological studies from Framingham,4 Iowa,5 Edinburgh,6 and most recently, Honolulu,7 have suggested that systemic hypertension, if untreated, can lead to cognitive decline. Full-fledged vascular dementia may be more widespread than originally thought, and some consider the diagnosis underutilized.8,9 Skoog et al.10 have even suggested that the prevalence of vascular dementia might be nearly as high as AD. Associations between hypertension and structural brain abnormalities have also been described.11 White matter lesions on Magnetic Resonance Imaging have been shown to relate to both hypertension and cognitive decline in older subjects,12 and elevated 24-hour ambulatory blood pressures have been associated with multiple lacunar strokes.13 A thorough review concluded that hypertension was associated with deficits in attention, memory, and abstract reasoning.14 The implications of these results are that many cases of incipient dementia might well be preventable, to the extent that cardiovascular and, specifically, cerebrovascular disease can impeded.15 In the context of the forgoing work, the epidemiological study by Dealberto et al. in this issue of the Journal16 implies that clinicians ought to consider yet another heretofore unrecognized cause of cognitive loss in old age: disordered breathing during sleep, often referred to simply as sleep apnea. At first glance, the notion that a sleep disorder could have any causal impact on waking cognitive function appears incongruous, or at very best, indirect. One might suspect, for example, that if ventilatory responsiveness to C02 was altered because of medullary dysfunction, this might be manifested during sleep because the state of sleep itself is associated with a mild hypercapnia. Sleep apnea, however, typically occurs in the context of normal hypercapnic drive and without C02 retention in individuals without known brainstem disease.17,18 Moreover, it is an exceedingly common condition in the older population.19,20 If this indirect pathway is discounted, how then might disordered breathing in sleep lead to cognitive loss? The mechanisms underlying sleep apnea and cardiovascular responses to apneic events are complex, and the reader is directed elsewhere for a more thorough description of how the cardiovascular system is regulated during sleep.17,18 Particularly relevant facts can be highlighted here. Sleep apnea is associated with transient rises and falls in systemic and pulmonary artery pressure as the sleeper attempts to overcome upper airway obstruction. This increased diaphragmatic effort leads to increased negative intrathoracic pressure, which results in left ventricular afterload and decreased cardiac output. Heart rate typically slows during apneic events and then elevates during resumption of breathing, and cardiac arrhythmias often occur. Arterial oxygen saturation also can fall during the apneic episodes depending on baseline PO2 and functional residual capacity. Increased sympathetic tone with elevated catecholamine levels often result. Neurobehaviorally, the frequent periodic arousals that occur as the sleeper awakens to resume breathing result in profound sleepiness during the daytime hours and the experience that the individual has slept poorly. Although the daytime behavioral effects are often considered to reflect the effects of severely interrupted and fragmented sleep, some evidence suggests that the brain, like the heart and kidney, may be a particularly relevant target organ for the hemodynamic and/or hypoxic changes in sleep. Several laboratory studies, for example, have shown cerebral perfusion during sleep is altered substantially in individuals with sleep apnea.21–25 There are also some epidemiological data suggesting that sleep apnea and snoring may be associated with stroke.26 In all likelihood, the laboratory-based studies showing associations between psychometrics and indices of sleep apnea severity27 can be considered to be reflective of such sleep fragmentation, hypoxia, and hemodynamic effects. See also p 1287 One of the contributions of the Dealberto et al. study is to extend what has been seen in small highly selected clinic populations evaluated in the laboratory during the last 10 years and apply it to the general population. In 1985, we reported that simple psychometrics similar to those reported by these authors were correlated with measures of sleep apnea in older patients studied in the sleep lab.28 In 1986, Berry et al.29 showed similar results in men who were heavy snorers. Since then a number of other groups have shown deficits in conjunction with sleep apnea, and possibly snoring as well, in areas as diverse as executive function, reaction time, psychomotor speed, and memory,30–36 though the results may be mitigated, to some extent, if the subjects under study are optimally healthy.37–42 At the population level, this phenomenon has been largely unexplored. Jennum et al.43 have noted that self reports of memory loss (rather than psychometrically assessed memory performance) were associated with snoring in a Danish population of 3323 men. A preliminary report by Swan et al.44 also noted correlations between reports of sleepiness and performances on measures such as the Benton Visual Retention Test, the Trailmaking Test, and delayed recall in the California Verbal Learning Test in a northern Californian cohort of 580 older men. The current study by Dealberto et al. represents the largest published study to date suggesting associations between symptoms of sleep apnea (excessive daytime sleepiness, nocturnal snoring) and psychometrically assessed cognitive impairment. While their study relies on symptoms of sleep apnea rather than physiologically measured sleep apnea, some overlap between symptoms and disease is likely.45,46 Several historical comments related to this topic may be illuminating. Clinicians have often noted the profound daytime sleepiness of the demented patient. Turn of the century Russian psychiatrists, though operating within a Pavlovian framework, went so far as to believe that inadequate sleep was associated causally with dementia. Comments such as the following bear witness to such a belief: “senility is caused by overstraining the main nerve processes in the cortex of the cerebrum but such damage can be repaired by much sleep” (as quoted in Ref. 47, p. 84). While Dealberto et al. do not claim to measure such cortical “strain,” they do invoke a construct not altogether that different, i.e., reported daytime sleepiness, which can be construed here as the brain's self-report of its own level of arousal. Numerous laboratory studies have demonstrated at least some correlation between such self-reports of sleepiness and objective, physiological measurements of sleep tendency.48,49 Similarly, while the Dealberto et al. study is not a treatment study, there are data, based largely on middle-aged sleep clinic patients, that suggest that nonsurgical treatment of this sleep disorder with continuous positive airway pressure may improve neuropsychologically assessed cognitive function50–53 or mood,54,55 particularly if alertness also improves. Several uncontrolled case reports suggest that adequate nocturnal treatment for sleep apnea may reverse dementia.56–58 Some geriatricians may find this whole discussion vaguely reminiscent of the Zeitgeist in the late 1960s when hyperbaric oxygen was thought to improve cognitive function,59 a finding that fell into disfavor as other researchers could not replicate the original finding.60–62 In this regard it important to stress that the hypoxia occurring with sleep apnea is transient (though repetitive) and nocturnal. And the changes in oxygen saturation may well not even be the most important components of this syndrome affecting brain function since the aforementioned changes in brain perfusion may be more relevant for cerebral vasculature. Growing awareness of these issues fits well with the upwelling perspective that at least some dementias in old age may be preventable by modification of cardiovascular risk factors, in this case, sleep apnea. Supported by Grants AG-10643 and AG-06066.