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Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, Albanese M, Mercuri NB, Izzi F, Bernardini S, Nitti A, Sancesario GM, Sica F, Marciani MG, Placidi F. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol. 2014 Dec;71(12):1498-505. PubMed.
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Washington University School of Medicine
This study significantly adds to our understanding about the relationship between sleep, orexin, and AD. The authors measure sleep more robustly than in other published studies with home sleep patterns reported via sleep diaries and an acclimation polysomnogram preceding the study polysomnogram. This is important because if there was only one night of polysomnography we could not say how representative it was of the participants' sleep at home. Further, the lumbar punctures were performed within a narrow time period.
The main findings of the study are: 1) CSF orexin concentration positively correlated with t-tau and p-tau; 2) CSF orexin levels correlated with several sleep parameters (wakefulness after sleep onset, sleep efficiency, percent of REM sleep, and sleep latency). The study provides additional evidence that sleep is disturbed in moderate-severe AD and that the orexinergic system is involved.
Given the lack of correlation between CSF orexin concentration and mild AD, I think the study suggests sleep disturbance is more likely to be a result of AD rather a key part of AD pathogenesis. Sleep disturbance in AD may be another measure of brain dysfunction, such as cognitive impairment. A 2013 study by my colleagues Drs. Ju and Holtzman at Washington University showed that cognitively normal adults with amyloid deposition had reduced sleep efficiency compared to cognitively normal adults without amyloid deposition; this study had a much large number of participants and showed a small but statistically significant reduction in sleep efficiency (Ju et al., 2014). It may be that larger sample sizes are needed to define differences in CSF orexin concentrations between the control and mild AD group.
References:
Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology--a bidirectional relationship. Nat Rev Neurol. 2014 Feb;10(2):115-9. Epub 2013 Dec 24 PubMed.
View all comments by Brendan LuceyMayo Clinic
Liguori and colleagues report increased orexin in CSF from patients with mild to moderate Alzheimer’s disease (MMSE score <21). In parallel, these patients also had impaired nocturnal sleep compared to controls and patients with mild AD (MMSE score ≥ 21). Interestingly, the authors found no significant difference between AD patients with mild versus those with moderate to severe AD. However, the numbers reveal an increase in CSF orexin by approximately 12 percent in the moderate to severe versus mild AD patients, hence if the authors had included more patients (increased the power) this difference may have been significant.
No gender-associated differences were present in the investigated cohort. In regard to sleep efficiency and cognitive performance, the authors, not too surprisingly, reported a positive association between sleep efficiency and MMSE scores in AD patients, and their findings of negative correlations between sleep efficiency as well as REM sleep percentage and CSF orexin levels validate the biological links between orexin levels and sleep patterns. Importantly, the authors also investigated potential links between CSF orexin and Ab42 levels and found no evidence thereof. Hence, this study could not confirm the earlier described link between orexin and Aβ in mice (Kang et al., 2009). Liguori et al., however, speculate that the lack of correlation may be due to the fact that Aβ42 levels in their AD patients may already have reached a plateau, as they found no difference in Aβ levels between AD patients with different disease severities. Hence, the lack of association between CSF Aβ and orexin levels doesn’t out-rule a biological link because the authors did, in fact, report that decreased Aβ levels were associated with sleep deterioration in a sample of their AD cohort with severity ranging from mild to moderate disease.
The study contains a detailed and well-performed polysomnographic assessment of various sleep variables in AD patients. Their findings, overall, add to the growing body of evidence supporting the notion of a dysregulated orexinergic system in AD patients, who frequently experience disturbed sleep patterns. The results are in line with previous reports, although results from different studies are at times conflicting. For instance, whereas Liguori et al. found no gender-associated differences in CSF orexin levels, we and others have reported increased levels in females versus males (Wennström et al., 2012; Schmidt et al., 2013). Gender-associated differences in sleep patterns were previously reported in a large study by Silva and colleagues (Silva et al., 2008). In our own study, we looked at AD patients with mild dementia (MMSE score ≥ 21), and similar to Liguori et al., we could not detect altered orexin levels when compared to controls in groups of mixed gender. Female AD patients, however, did present significantly higher CSF orexin levels compared to controls (Wennström et al., 2012). Hence CSF orexin levels may not be sensitive to pathological changes until these become severe and group comparisons may have to be strictly stratified for confounding factors like gender. The interpretation of the results from human studies are complicated, as basic descriptive studies are lacking, for instance in regard to potential gender differences in the number of orexin-producing neurons in the hypothalamus, as well as how decreased CSF orexin levels relate to neurodegeneration. The results presented by Liguori et al. clearly demonstrate and support a role for a dysregulation of the orexinergic system in AD, but in order to further improve our understanding of the underlying molecular pathways, studies combining postmortem brain tissue and antemortem CSF analysis of patients progressing from mild cognitive impairment to AD are crucial. Also, since individuals carrying the APOE4 allele are known to accumulate Aβ pathology even in the absence of cognitive symptoms (Morris et al., 2010), it would be interesting to include APOE4-positive narcolepsy patients, in which a specific loss of orexin-producing cells is paralleled by decreased CSF orexin levels, in future studies of potential associations between orexin, wakefulness, Aβ levels, and plaque pathology.
References:
Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009 Nov 13;326(5955):1005-7. PubMed.
Wennström M, Londos E, Minthon L, Nielsen HM. Altered CSF Orexin and α-Synuclein Levels in Dementia Patients. J Alzheimers Dis. 2012 Jan 1;29(1):125-32. PubMed.
Schmidt FM, Kratzsch J, Gertz HJ, Tittmann M, Jahn I, Pietsch UC, Kaisers UX, Thiery J, Hegerl U, Schönknecht P. Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. PLoS One. 2013;8(5):e63136. Print 2013 PubMed.
Silva A, Andersen ML, De Mello MT, Bittencourt LR, Peruzzo D, Tufik S. Gender and age differences in polysomnography findings and sleep complaints of patients referred to a sleep laboratory. Braz J Med Biol Res. 2008 Dec;41(12):1067-75. PubMed.
Wennström M, Londos E, Minthon L, Nielsen HM. Altered CSF Orexin and α-Synuclein Levels in Dementia Patients. J Alzheimers Dis. 2012 Jan 1;29(1):125-32. PubMed.
Morris JC, Roe CM, Xiong C, Fagan AM, Goate AM, Holtzman DM, Mintun MA. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann Neurol. 2010 Jan;67(1):122-31. PubMed.
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