Dementia Therapy: Sleeping Duty

20. February 2015
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For people who present with low oxygen saturation in the blood at night or spend little time in deep sleep, the risk of dementia-associated changes occurring in the brain, such as microinfarcts and brain atrophy, increases.

Dr. Rebecca Gelber of the Pacific Health Research & Education Institute in Honolulu, Hawaii, and her colleagues analysed via autopsy the brains of 167 men who had during their lifetime been examined polysomnographically. Men who had shown low oxygen saturation over most of the night were observed at autopsy to have had microinfarcts more than three times more frequently than men whose reduced oxygenation at night was measurably shown to have occurred for only a short period of time.

Does deep sleep protect against cell death?

The authors further established that men who had spent little time in deep sleep (slow-wavesleep, NREM sleep stage N3) suffered more than twice as frequently from generalised brain atrophy. Deep sleep plays a crucial role in the processing of new memories, however with increasing age the proportion of deep sleep as part of total sleep time drops.

The study participants were on average 84 years old when they were polysomnographically examined, and died on average 6.4 years later. At autopsy various brain lesion parameters were identified, for example microinfarcts, generalised brain atrophy, Lewy bodies, the number of amyloid plaques and neurofibrillary tangles, as well as the degeneration of the locus caeruleus. In contrast to that for microinfarctions and atrophy, the researchers could find no relationship between the examined sleep parameters and lesions typical for Alzheimer’s as well as Lewy bodies.

More sleep, less Alzheimer’s protein

Meanwhile the evidence of a link between too little or poor sleep and an increased risk of Alzheimer’s has been accumulating. As early as 2009 Dr. Jae Eun Kang and her colleagues at the University of Washington published a study in Science, in which they were able to show that in transgenic Alzheimer mice with chronic sleep deprivation beta-amyloid plaque loads increase significantly. In a 2013 study published in Science, Dr. Lulu Xie and her team at University Rochester in the US revealed a mechanistic explanation for the restorative function of sleep in mice: neurotoxic metabolites such as beta-amyloids are removed more quickly from the brain during sleep than during waking states.

Human studies, however, are still scarce. In August 2014 Sharon Ooms of the University Hospital Nijmegen in the Netherlands published a study of 26 healthy men. One half had to stay awake for an entire night while the other half was allowed to sleep normally. By using an intrathecal catheter spinal fluid samples were taken and analysed at regular intervals for their content of amyloid beta 42 peptide (Aβ42). Despite the small number of study participants, the authors observed a statistically significant association between sleep duration and morning Aβ42 levels in the cerebrospinal fluid: Whereas the Aβ42 concentration levels among the sleepers fell by six percent over the night, this was not the case among the men who remained awake.

Using the air pump against the forgetting process

But what conclusions can be drawn from these studies for the treatment of sleep disorders and dementia? Dr Sonia Ancoli-Israel and her colleagues from UCSD, California, in a study in 2008 already came to the conclusion that the treatment of obstructive sleep apnea using CPAP may improve cognitive performance of Alzheimer’s patients, even when dementia was already detectable.

Nevertheless, this is so far the only study of its kind, and it demonstrates some methodological weaknesses. In particular, the small group size of only 52 patients and the short CPAP treatment period of six weeks complicates the interpretation of the data. In addition a follow-up study which was designed to demonstrate the protective effect on cognitive performance using a longer-term CPAP treatment is, due to the study design, limited in its ability to yield information.

Professor Kathy Richards of George Mason University in Virginia, USA, has therefore strongly called for a randomised controlled trial in which the long-term effects of Alzheimer’s disease treatment and obstructive sleep apnea syndrome treatment using CPAP ought to be examined. “Stabilising the cognitive abilities of Alzheimer’s patients could help in maintaining the independence of patients, in delaying admission to nursing homes, in reducing the burden on caregivers and on health care costs”, explains Prof. Richards.

Causal relationship so far unproven

The authors of the current study also caution against misinterpreting the cause-effect relationship involved in the correlation uncovered between poor sleep and dementia-related brain damage. “Further studies are needed in order to elucidate how deep sleep may play a restorative role in brain function, and whether the prevention of low oxygen saturation can reduce the risk of dementia,” says Dr. Gelber.

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