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Sleep spindles, K-complexes, limb movements and sleep stage proportions may be biomarkers for amnestic mild cognitive impairment and Alzheimer’s disease

Sleep and Breathing volume 24, pages 637–651 (2020)Cite this article

Abstract

Purpose

Sleep disturbances are common in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients. Non-rapid eye movement stage 3 (N3), rapid eye movement stage (REM), spindle density, and K-complex (KC) density are decreased in MCI and AD patients. Periodic limb movements in sleep (PLMS) are increased in other neurodegenerative diseases. We aimed to distinguish amnestic mild cognitive impairment (aMCI) patients from the overall population of MCI patients by comparing the N3 and REM proportions, the morphological characteristics of spindles and KCs and the periodic limb movement index (PLMI) among control, aMCI and AD subjects.

Methods

In 92 subjects (30 controls, 32 aMCI and 30 AD), sleep stages, spindles, KCs and PLMS were recorded during the second of two nights of polysomnography (PSG). We compared the above parameters among the three groups.

Results

AD and aMCI subjects had lower proportions of N3 and REM, poorer spindle and KC activities and more frequent PLMS than controls. These alterations were associated with decreased Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. We determined cut-off values for distinguishing aMCI and AD using logistic regression and receiver operating characteristic (ROC) analyses.

Conclusions

AD and aMCI patients have abnormal sleep stage proportions, spindles, KCs and PLMS. The combination of the above alterations may distinguish aMCI and AD patients from controls with high specificity and sensitivity.

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Abbreviations

AD:

Alzheimer’s disease

aMCI:

mild cognitive impairment

NC:

normal elderly control subjects

ANOVA:

analysis of variance

EEG:

electroencephalography

PLMS:

Periodic limb movements in sleep

NREM:

non-rapid eye movement sleep

REM:

rapid eye movement sleep

TST:

total sleep time

SL:

sleep latency

REML:

rapid eye movement sleep latency

WASO:

wakefulness after sleep onset

EOG:

electrooculography

ECG:

electrocardiography

CSF:

cerebrospinal fluid

Aβ1-42 :

amyloid β-protein 1–42

t-tau:

total tau

p-tau181 :

phosphorylated tau 181

ROC:

receiver operating characteristic

AUC:

area under the curve

References

  1. Gutierrez A, Vitorica J (2018) Toward a new concept of Alzheimer's disease models: a perspective from neuroinflammation. J Alzheimers Dis 64(s1):S329–S338

    CAS  Google Scholar 

  2. Wimo A, Jonsson L, Bond J, Prince M, Winblad B (2013) The worldwide economic impact of dementia 2010. Alzheimers Dement 9(1):1–11

    Google Scholar 

  3. Gunn DG, Naismith SL, Terpening Z, Lewis SJ (2014) The relationships between poor sleep efficiency and mild cognitive impairment in Parkinson disease. J Geriatr Psychiatry Neurol 27(2):77–84

    Google Scholar 

  4. Malone C, Deason RG, Palumbo R, Heyworth N, Tat M, Budson AE (2018) False memories in patients with mild cognitive impairment and mild Alzheimer's disease dementia: can cognitive strategies help? J Clin Exp Neuropsychol 41(2):204–218

    Google Scholar 

  5. Ansai JH, Andrade LP, Rossi PG, Takahashi ACM, Vale FAC, Rebelatto JR (2017) Gait, dual task and history of falls in elderly with preserved cognition, mild cognitive impairment, and mild Alzheimer's disease. Braz J Phys Ther 21(2):144–151

    Google Scholar 

  6. Mander BA, Winer JR, Walker MP (2017) Sleep and human aging. Neuron 94(1):19–36

    CAS  Google Scholar 

  7. Hu M, Zhang P, Li C, Tan Y, Li G, Xu D, Chen L (2017) Sleep disturbance in mild cognitive impairment: a systematic review of objective measures. Neurol Sci 38(8):1363–1371

    Google Scholar 

  8. Mander BA, Winer JR, Jagust WJ, Walker MP (2016) Sleep: a novel mechanistic pathway, biomarker, and treatment target in the pathology of Alzheimer's disease? Trends Neurosci 39(8):552–566

    CAS  Google Scholar 

  9. Westerberg CE, Mander BA, Florczak SM, Weintraub S, Mesulam MM, Zee PC, Paller KA (2012) Concurrent impairments in sleep and memory in amnestic mild cognitive impairment. J Int Neuropsychol Soc 18(03):490–500

    Google Scholar 

  10. Mander BA, Zhu AH, Lindquist JR, Villeneuve S, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP (2017) White matter structure in older adults moderates the benefit of sleep spindles on motor memory consolidation. J Neurosci 37(48):11675–11687

    CAS  Google Scholar 

  11. Ju YS, Ooms SJ, Sutphen C, Macauley SL, Zangrilli MA, Jerome G, Fagan AM, Mignot E, Zempel JM, Claassen JAHR, Holtzman DM (2017) Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain 140(8):2104–2111

    Google Scholar 

  12. Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP (2015) β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 18(7):1051–1057

    CAS  Google Scholar 

  13. De Gennaro L, Ferrara M (2003) Sleep spindles: an overview. Sleep Med Rev 7(5):423–440

    Google Scholar 

  14. Crowley K, Trinder J, Colrain IM (2002) An examination of evoked K-complex amplitude and frequency of occurrence in the elderly. J Sleep Res 11(2):129–140

    Google Scholar 

  15. Cairney SA, Guttesen AÁV, El Marj N, Staresina BP (2018) Memory consolidation is linked to spindle-mediated information processing during sleep. Curr Biol 28(6):948–954

    CAS  Google Scholar 

  16. Gorgoni M, Lauri G, Truglia I, Cordone S, Sarasso S, Scarpelli S, Mangiaruga A, Atri DA et al (2016) Parietal fast sleep spindle density decrease in Alzheimer’s disease and amnesic mild cognitive impairmenT. Neural Plast 2016:1–10

    Google Scholar 

  17. Reda F, Gorgoni M, Lauri G, Truglia I, Cordone S, Scarpelli S, Mangiaruga A, D'Atri A et al (2017) In Search of sleep biomarkers of Alzheimer’s disease: K-complexes do not discriminate between patients with mild cognitive impairment and healthy controls. Brain Sci 7(12):51

    Google Scholar 

  18. De Gennaro L, Gorgoni M, Reda F, Lauri G, Truglia I, Cordone S, Scarpelli S, Mangiaruga A et al (2017) The fall of sleep K-complex in Alzheimer disease. Sci Rep 7(1):39688

    Google Scholar 

  19. Taillard J, Sagaspe P, Berthomier C, Brandewinder M, Amieva H, Dartigues J, Rainfray M, Harston S et al (2019) Non-REM sleep characteristics predict early cognitive impairment in an aging population. Front Neurol 10:197

    Google Scholar 

  20. Schilling C, Schlipf M, Spietzack S, Rausch F, Eisenacher S, Englisch S, Reinhard I, Haller L, Grimm O, Deuschle M, Tost H, Zink M, Meyer-Lindenberg A, Schredl M (2017) Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype. Eur Arch Psychiatry Clin Neurosci 267(3):213–224

    Google Scholar 

  21. Gorgoni M, Reda F, D'Atri A, Scarpelli S, Ferrara M, De Gennaro L (2019) The heritability of the human K-complex: a twin study. Sleep 42(6)

  22. Natarajan R (2010) Review of periodic limb movement and restless leg syndrome. J Postgrad Med 56(2):157–162

    CAS  Google Scholar 

  23. Wu M, Tseng P, Chen T, Chen Y, Liou L, Lin P, Hsu C (2018) The efficacy and tolerability of rotigotine on patients with periodic limb movement in sleep: a systematic review and meta-analysis. PLoS One 13(4):e195473

    Google Scholar 

  24. Högl B, Stefani A (2017) Restless legs syndrome and periodic leg movements in patients with movement disorders: specific considerations. Mov Disord 32(5):669–681

    Google Scholar 

  25. Chwiszczuk L, Breitve M, Hynninen M, Gjerstad MD, Aarsland D, Rongve A (2016) Higher frequency and complexity of sleep disturbances in dementia with Lewy bodies as compared to Alzheimer's disease. Neurodegener Dis 16(3-4):152–160

    CAS  Google Scholar 

  26. Albers JA, Chand P, Anch AM (2017) Multifactorial sleep disturbance in Parkinson's disease. Sleep Med 35:41–48

    Google Scholar 

  27. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3):183–194

    CAS  Google Scholar 

  28. Association AP (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Publishing, Washington

    Google Scholar 

  29. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CJ, Kawas CH, Klunk WE, Koroshetz WJ et al (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7(3):263–269

    Google Scholar 

  30. Hamilton M (1967) Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 4(6):278–296

    Google Scholar 

  31. Klem GH, Luders HO, Jasper HH, Elger C (1999) The ten-twenty electrode system of the International Federation. The International Federation of Clinical Neurophysiology. Electroencephalogr Clin Neurophysiol Suppl 52:3–6

    CAS  Google Scholar 

  32. Iber C, Ancoli-Israel S, Chesson A, Quan S (2007) for the American Academyof Sleep Medicine. The AASM manual for the scoring of sleep and associated events; rules, terminology and technical specifcations, 1st edn. American Academy of Sleep Medicine, Westchester

    Google Scholar 

  33. Molle M, Marshall L, Gais S, Born J (2002) Grouping of spindle activity during slow oscillations in human non-rapid eye movement sleep. J Neurosci 22(24):10941–10947

    CAS  Google Scholar 

  34. Bastien CH, St-Jean G, Turcotte I, Morin CM, Lavallee M, Carrier J, Forget D (2009) Spontaneous K-complexes in chronic psychophysiological insomnia. J Psychosom Res 67(2):117–125

    Google Scholar 

  35. Crowley K, Trinder J, Kim Y, Carrington M, Colrain IM (2002) The effects of normal aging on sleep spindle and K-complex production. Clin Neurophysiol 113(10):1615–1622

    Google Scholar 

  36. Hashemi NS, Dehnavi F, Moghimi S, Ghorbani M (2019) Slow spindles are associated with cortical high frequency activity. Neuroimage 189:71–84

    Google Scholar 

  37. Molle M, Bergmann TO, Marshall L, Born J (2011) Fast and slow spindles during the sleep slow oscillation: disparate coalescence and engagement in memory processing. Sleep 34(10):1411–1421

    Google Scholar 

  38. Guo S, Huang J, Jiang H, Han C, Li J, Xu X, Zhang G, Lin Z et al (2017) Restless legs syndrome: from pathophysiology to clinical diagnosis and management. Front Aging Neurosci 9:171

    Google Scholar 

  39. Amelio DM, Puglisi-Allegra S, Mercuri N (2018) The role of dopaminergic midbrain in Alzheimer’s disease: translating basic science into clinical practice. Pharmacol Res 130:414–419

    Google Scholar 

  40. Hibi S, Yamaguchi Y, Umeda-Kameyama Y, Yamamoto H, Iijima K, Momose T, Akishita M, Ouchi Y (2012) The high frequency of periodic limb movements in patients with Lewy body dementia. J Psychiatr Res 46(12):1590–1594

    Google Scholar 

  41. Roberts RO, Knopman DS, Geda YE, Cha RH, Roger VL, Petersen RC (2010) Coronary heart disease is associated with non-amnestic mild cognitive impairment. Neurobiol Aging 31(11):1894–1902

    Google Scholar 

  42. Oltra-Cucarella J, Delgado S, Duque P, Pérez-Vicente JA, Cabello-Rodríguez L (2018) Encoding deficits in low-educated individuals with non-amnestic mild cognitive impairment. Analysis of memory processes using the Item Specific Deficit Approach. Psychiatry Res 268:211–216

    Google Scholar 

  43. Boyce R, Williams S, Adamantidis A (2017) REM sleep and memory. Curr Opin Neurobiol 44:167–177

    CAS  Google Scholar 

  44. Skelin I, Kilianski S, McNaughton BL (2019) Hippocampal coupling with cortical and subcortical structures in the context of memory consolidation. Neurobiol Learn Mem 160:21–31

    Google Scholar 

  45. Paraskevaidi M, Morais C, Halliwell DE, Mann D, Allsop D, Martin-Hirsch PL, Martin FL (2018) Raman spectroscopy to diagnose Alzheimer's disease and dementia with Lewy bodies in blood. ACS Chem Neurosci 9(11):2786–2794

    CAS  Google Scholar 

  46. Crowley K (2004) Evoked K-complex generation: the impact of sleep spindles and age. Clin Neurophysiol 115(2):471–476

    Google Scholar 

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Acknowledgments

We thank all the subjects for participating in this study and the support by The Sixth Affiliated Hospital of Sun Yat-Sen University.

Author information

Affiliations

  1. Department of Neurology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510655, China

    Shunjie Liu, Ke Tang, Qingfeng Lei, Lu He, Yangyang Meng, Xiaodong Cai & Zhong Li

  2. Department of Psychology, Sun Yat-sen University, Guangzhou, 510006, China

    Junhao Pan

  3. Shenzhen Research Institute, Sun Yat-Sen University, Shenzhen, China

    Zhong Li

  4. Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510080, China

    Zhong Li

Authors
  1. Shunjie Liu
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  2. Junhao Pan
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  3. Ke Tang
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  4. Qingfeng Lei
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  5. Lu He
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Correspondence to Zhong Li.

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Declaration

All authors have approved the final manuscript for submission.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The ethical committee of The Sixth Affiliated Hospital of Sun Yat-Sen University approved this study, and the study was carried out in accordance with the Declaration of Helsinki.

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All subjects gave their written informed consent to participate in the study.

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Comments

The work is interesting and creates the potential in the field for new Biomarkers for Amnestic Mild Cognitive Impairment and Alzheimer’s disease. Based on this work, more signal processing advances could be applied and generalize further the findings.

Leontios Hadjileontiadis

Thessaloniki, Greece

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Cite this article

Liu, S., Pan, J., Tang, K. et al. Sleep spindles, K-complexes, limb movements and sleep stage proportions may be biomarkers for amnestic mild cognitive impairment and Alzheimer’s disease. Sleep Breath 24, 637–651 (2020). https://doi.org/10.1007/s11325-019-01970-9

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  • DOI: https://doi.org/10.1007/s11325-019-01970-9

Keywords

  • Alzheimer’s disease
  • Amnestic mild cognitive impairment
  • Polysomnography
  • Sleep spindle
  • K-complex
  • Periodic limb movements
  • Sleep stages