Table Info

Table 4.

Sleep quality and DTI

Diffusion Tensor Measure	Model 1 HFC (P)	Model 2 HFC (P)	Model 3 HFC (P)	Model 1 LFC (P)	Model 2 LFC (P)	Model 3 LFC (P)	Model 1 Wake (P)	Model 2 Wake (P)	Model 3 Wake (P)
FA	0.25	0.03	0.03	0.83	0.11	0.11	0.29	0.12	0.15
MD	0.05	0.01	0.01	0.80	0.23	0.20	0.13	0.01	0.02
PSMD	0.41	0.28	0.26	0.70	0.31	0.25	0.60	0.58	0.86

Moderating effects of gender

Diffusion Tensor Measure	Model 1 HFC (P)	Model 2 HFC (P)	Model 3 HFC (P)	Model 1 LFC (P)	Model 2 LFC (P)	Model 3 LFC (P)	Model 1 Wake (P)	Model 2 Wake (P)	Model 3 Wake (P)

FA	-	-	0.14	-	-	0.22	-	-	0.22
MD	-	-	0.48	-	-	0.50	-	-	0.15
PSMD	-	-	0.005	-	-	0.02	-	-	0.19

Fully adjusted model shown for gender; statistical significance is shown. Model 1: unadjusted; Model 2: adjusted for age and gender; Model 3: adjusted for diabetes, hypertension, hyperlipidemia, body mass index; -: only full model computed

Declarations

Author contributions

RJT conceptualized the study design and analysis and drafted the manuscript; PM provided technical MRI details, and critically reviewed the manuscript; HK performed statistical analysis and reviewed the manuscript, EJH interpreted raw data and reviewed the manuscript, CSD was responsible for the brain imaging and reviewed the manuscript, CK and TFAA organized, managed, and analyzed data and reviewed the manuscript, RA conceptualized the study design, organized the data collection, and reviewed the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Conflicts of interest

Dr. Thomas reports patent and licenses with royalties from MyCardio, LLC, for the ECG-spectrogram, unlicensed patent for a CO2 regulating device for treatment of central and complex sleep apnea, license with royalties’ from DeVibiss-Drive for an auto-CPAP algorithm, and a general sleep medicine consultant for Guidepoint Global and GLG Councils. Dr. Au has no conflicts of interest but is on the Scientific Advisory Board of Signant Health and is a scientific consultant to Biogen. The other authors declare that they have no conflicts of interest.

Ethical approval

The research study was approved by the Institutional Review Boards of the Beth Israel Deaconess Medical Center (2103P000121) and Boston University (H-32375).

Consent to participate

The informed consent to participate in the study was obtained from all participants.

Consent to publication

Not applicable.

Availability of data and materials

The data supporting this report can be obtained through standard processes from the Framingham Heart Study Service Center. https://framinghamheartstudy.org/fhs-for-researchers/fhs-service-center/

Funding

Support was provided by the Beth Israel Deaconess Medical center Chief Academic Officer’s Innovation Fund, the Framingham Heart Study’s National Heart, Lung, and Blood Institute contract (N01-HC-25195; HHSN268201500001I), by grants (R01-AG016495, R01-AG008122, R01-AG033040, R01-AG054156; R56 AG062109) from the National Institute on Aging, and by grant (R01-NS017950) from the National Institute of Neurological Disorders and Stroke and a grant from Pfizer. The study sponsors had no role in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.

Copyright

References

Unruh ML, Redline S, An MW, Buysse DJ, Nieto FJ, Yeh JL, et al. Subjective and objective sleep quality and aging in the sleep heart health study. J Am Geriatr Soc. 2008;56:1218–27. [DOI] [PubMed]

Ancoli-Israel S, Alessi C. Sleep and aging. Am J Geriatr Psychiatry. 2005;13:341–3. [DOI] [PubMed]

Cajochen C, Munch M, Knoblauch V, Blatter K, Wirz-Justice A. Age-related changes in the circadian and homeostatic regulation of human sleep. Chronobiol Int. 2006;23:461–74. [DOI] [PubMed]

Munch M, Knoblauch V, Blatter K, Wirz-Justice A, Cajochen C. Is homeostatic sleep regulation under low sleep pressure modified by age? Sleep. 2007;30:781–92. [DOI] [PubMed] [PMC]

Rytkonen KM, Wigren HK, Kostin A, Porkka-Heiskanen T, Kalinchuk AV. Nitric oxide mediated recovery sleep is attenuated with aging. Neurobiol Aging. 2010;31:2011–9. [DOI] [PubMed]

Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep. 2002;25:268–76. [DOI] [PubMed]

Bonnet MH, Arand DL. Clinical effects of sleep fragmentation versus sleep deprivation. Sleep Med Rev. 2003;7:297–310. [DOI] [PubMed]

Bonnet MH. Cognitive effects of sleep and sleep fragmentation. Sleep. 1993;16 Suppl 8:S65–7. [DOI] [PubMed]

Bonnet MH. The effect of sleep fragmentation on sleep and performance in younger and older subjects. Neurobiol Aging. 1989;10:21–5. [DOI] [PubMed]

10.

Ferrie JE, Shipley MJ, Akbaraly TN, Marmot MG, Kivimaki M, Singh-Manoux A. Change in sleep duration and cognitive function: findings from the whitehall II study. Sleep. 2011;34:565–73. [DOI] [PubMed] [PMC]

11.

Leng Y, Blackwell T, Stone KL, Hoang TD, Redline S, Yaffe K. Periodic limb movements in sleep are associated with greater cognitive decline in older men without dementia. Sleep. 2016;39:1807–10. [DOI] [PubMed] [PMC]

12.

Song Y, Blackwell T, Yaffe K, Ancoli-Israel S, Redline S, Stone KL, et al. Relationships between sleep stages and changes in cognitive function in older men: the MrOS Sleep Study. Sleep. 2015;38:411–21. [DOI] [PubMed] [PMC]

13.

Spira AP, Stone KL, Redline S, Ensrud KE, Ancoli-Israel S, Cauley JA, et al. Actigraphic sleep duration and fragmentation in older women: associations with performance across cognitive domains. Sleep. 2017;40:zsx073. [DOI]

14.

De Gennaro L, Gorgoni M, Reda F, Lauri G, Truglia I, Cordone S, et al. The fall of sleep K-complex in Alzheimer disease. Sci Rep. 2017;7:39688. [DOI] [PubMed] [PMC]

15.

Bigler ED, Lowry CM, Kerr B, Tate DF, Hessel CD, Earl HD, et al. Role of white matter lesions, cerebral atrophy, and APOE on cognition in older persons with and without dementia: the Cache County, Utah, study of memory and aging. Neuropsychology. 2003;17:339–52. [DOI] [PubMed]

16.

Chondrogiorgi M, Astrakas LG, Zikou AK, Weis L, Xydis VG, Antonini A, et al. Multifocal alterations of white matter accompany the transition from normal cognition to dementia in Parkinson’s disease patients. Brain Imaging Behav. 2019;13:232–40. [DOI] [PubMed]

17.

Kertesz A, Polk M, Carr T. Cognition and white matter changes on magnetic resonance imaging in dementia. Arch Neurol. 1990;47:387–91. [DOI] [PubMed]

18.

Power MC, Su D, Wu A, Reid RI, Jack CR, Knopman DS, et al. Association of white matter microstructural integrity with cognition and dementia. Neurobiol Aging. 2019;83:63–72. [DOI] [PubMed] [PMC]

19.

Yaffe K, Nasrallah I, Hoang TD, Lauderdale DS, Knutson KL, Carnethon MR, et al. Sleep duration and white matter quality in middle-aged adults. Sleep. 2016;39:1743–7. [DOI] [PubMed] [PMC]

20.

Ho BL, Tseng PT, Lai CL, Wu MN, Tsai MJ, Hsieh CF, et al. Obstructive sleep apnea and cerebral white matter change: a systematic review and meta-analysis. J Neurol. 2018;265:1643–53. [DOI] [PubMed]

21.

Kumar R, Pham TT, Macey PM, Woo MA, Yan-Go FL, Harper RM. Abnormal myelin and axonal integrity in recently diagnosed patients with obstructive sleep apnea. Sleep. 2014;37:723–32. [DOI] [PubMed] [PMC]

22.

Castronovo V, Scifo P, Castellano A, Aloia MS, Iadanza A, Marelli S, et al. White matter integrity in obstructive sleep apnea before and after treatment. Sleep. 2014;37:1465–75. [DOI] [PubMed] [PMC]

23.

Xiong Y, Zhou XJ, Nisi RA, Martin KR, Karaman MM, Cai K, et al. Brain white matter changes in CPAP-treated obstructive sleep apnea patients with residual sleepiness. J Magn Reson Imaging. 2017;45:1371–8. [DOI] [PubMed] [PMC]

24.

Jak AJ, Preis SR, Beiser AS, Seshadri S, Wolf PA, Bondi MW, et al. Neuropsychological criteria for mild cognitive impairment and dementia risk in the framingham heart study. J Int Neuropsychol Soc. 2016;22:937–43. [DOI] [PubMed] [PMC]

25.

Ashry A, Hilmisson H, Ni Y, Thomas RJ. Automated apnea-hypopnea index from oximetry and spectral analysis of cardiopulmonary coupling. Ann Am Thorac Soc. 2021;[Epub ahead of print]. [DOI]

26.

Thomas RJ, Mietus JE, Peng CK, Gilmartin G, Daly RW, Goldberger AL, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep. 2007;30:1756–69. [DOI] [PubMed] [PMC]

27.

Thomas RJ, Mietus JE, Peng CK, Goldberger AL. An electrocardiogram-based technique to assess cardiopulmonary coupling during sleep. Sleep. 2005;28:1151–61. [DOI] [PubMed]

28.

Thomas RJ, Mietus JE, Peng CK, Guo D, Gozal D, Montgomery-Downs H, et al. Relationship between delta power and the electrocardiogram-derived cardiopulmonary spectrogram: possible implications for assessing the effectiveness of sleep. Sleep Med. 2014;15:125–31. [DOI] [PubMed] [PMC]

29.

Wood C, Bianchi MT, Yun CH, Shin C, Thomas RJ. Multicomponent analysis of sleep using electrocortical, respiratory, autonomic and hemodynamic signals reveals distinct features of stable and unstable NREM and REM sleep. Front Physiol. 2020;11:592978. [DOI] [PubMed] [PMC]

30.

Parrino L, Grassi A, Milioli G. Cyclic alternating pattern in polysomnography: what is it and what does it mean? Curr Opin Pulm Med. 2014;20:533–41. [DOI] [PubMed]

31.

Jenkinson M, Beckmann CF, Behrens TE, Woolrich MW, Smith SM. FSL. Neuroimage. 2012;62:782–90. [DOI] [PubMed]

32.

Baykara E, Gesierich B, Adam R, Tuladhar AM, Biesbroek JM, Koek HL, et al. A novel imaging marker for small vessel disease based on skeletonization of white matter tracts and diffusion histograms. Ann Neurol. 2016;80:581–92. [DOI] [PubMed]

33.

Nicolas R, Hiba B, Dilharreguy B, Barse E, Baillet M, Edde M, et al. Changes over time of diffusion MRI in the white matter of aging brain, a good predictor of verbal recall. Front Aging Neurosci. 2020;12:218. [DOI] [PubMed] [PMC]

34.

Deary IJ, Ritchie SJ, Munoz Maniega S, Cox SR, Valdes Hernandez MC, Luciano M, et al. Brain peak width of skeletonized mean diffusivity (PSMD) and cognitive function in later life. Front Psychiatry. 2019;10:524. [DOI] [PubMed] [PMC]

35.

Brueggen K, Dyrba M, Kilimann I, Henf J, Hoffmann W, Thyrian JR, et al. Hippocampal mean diffusivity for the diagnosis of dementia and mild cognitive impairment in primary care. Curr Alzheimer Res. 2018;15:1005–12. [DOI] [PubMed]

36.

Chen HL, Lu CH, Lin HC, Chen PC, Chou KH, Lin WM, et al. White matter damage and systemic inflammation in obstructive sleep apnea. Sleep. 2015;38:361–70. [DOI] [PubMed] [PMC]

37.

Lee MH, Yun CH, Min A, Hwang YH, Lee SK, Kim DY, et al. Altered structural brain network resulting from white matter injury in obstructive sleep apnea. Sleep. 2019;42:zsz120. [DOI] [PubMed]

38.

Tummala S, Palomares J, Kang DW, Park B, Woo MA, Harper RM, et al. Global and regional brain non-gaussian diffusion changes in newly diagnosed patients with obstructive sleep apnea. Sleep. 2016; 39:51–7. [DOI] [PubMed] [PMC]

39.

Zhang B, Zhu DM, Zhao W, Zhang Y, Yang Y, Zhang C, et al. Selective microstructural integrity impairments of the anterior corpus callosum are associated with cognitive deficits in obstructive sleep apnea. Brain Behav. 2019;9:e01482. [DOI] [PubMed] [PMC]

40.

Kozora E, Filley CM, Erkan D, Ulug AM, Vo A, Ramon G, et al. Longitudinal evaluation of diffusion tensor imaging and cognition in systemic lupus erythematosus. Lupus. 2018;27:1810–8. [DOI] [PubMed]

41.

Kraus MF, Susmaras T, Caughlin BP, Walker CJ, Sweeney JA, Little DM. White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain. 2007;130:2508–19. [DOI] [PubMed]

42.

van Norden AG, de Laat KF, van Dijk EJ, van Uden IW, van Oudheusden LJ, Gons RA, et al. Diffusion tensor imaging and cognition in cerebral small vessel disease: the RUN DMC study. Biochim Biophys Acta. 2012;1822:401–7. [DOI] [PubMed]

43.

Xu Q, Zhou Y, Li YS, Cao WW, Lin Y, Pan YM, et al. Diffusion tensor imaging changes correlate with cognition better than conventional MRI findings in patients with subcortical ischemic vascular disease. Dement Geriatr Cogn Disord. 2010;30:317–26. [DOI] [PubMed]

44.

Kumar R, Chavez AS, Macey PM, Woo MA, Yan-Go FL, Harper RM. Altered global and regional brain mean diffusivity in patients with obstructive sleep apnea. J Neurosci Res. 2012;90:2043–52. [DOI] [PubMed] [PMC]

45.

Kim H, Yun CH, Thomas RJ, Lee SH, Seo HS, Cho ER, et al. Obstructive sleep apnea as a risk factor for cerebral white matter change in a middle-aged and older general population. Sleep. 2013;36:709–15B. [DOI] [PubMed] [PMC]

46.

Lee S, Thomas RJ, Kim H, Seo HS, Baik I, Yoon DW, et al. Association between high nocturnal blood pressure and white matter change and its interaction by obstructive sleep apnoea among normotensive adults. J Hypertens. 2014;32:2005–12; discussion 12. [DOI] [PubMed]

47.

Macey PM, Kumar R, Yan-Go FL, Woo MA, Harper RM. Sex differences in white matter alterations accompanying obstructive sleep apnea. Sleep. 2012;35:1603–13. [DOI] [PubMed] [PMC]

48.

Valipour A. Gender-related differences in the obstructive sleep apnea syndrome. Pneumologie. 2012;66:584–8. [DOI] [PubMed]

49.

Bonsignore MR, Saaresranta T, Riha RL. Sex differences in obstructive sleep apnoea. Eur Respir Rev. 2019;28:190030. [DOI] [PubMed]

50.

Ferretti MT, Martinkova J, Biskup E, Benke T, Gialdini G, Nedelska Z, et al. Sex and gender differences in Alzheimer’s disease: current challenges and implications for clinical practice: position paper of the Dementia and Cognitive Disorders Panel of the European Academy of Neurology. Eur J Neurol. 2020;27:928–43. [DOI] [PubMed]

51.

Mielke MM. Sex and gender differences in Alzheimer’s disease dementia. Psychiatr Times. 2018;35:14–7. [PubMed] [PMC]

52.

Thurston RC, Wu M, Aizenstein HJ, Chang Y, Barinas Mitchell E, Derby CA, et al. Sleep characteristics and white matter hyperintensities among midlife women. Sleep. 2020;43:zsz298. [DOI] [PubMed] [PMC]

53.

Goff EA, Nicholas CL, Simonds AK, Trinder J, Morrell MJ. Differential effects of waking from non-rapid eye movement versus rapid eye movement sleep on cardiovascular activity. J Sleep Res. 2010;19:201–6. [DOI] [PubMed]

54.

O’Brien E. Dipping comes of age: the importance of nocturnal blood pressure. Hypertension. 2009;53:446–7. [DOI] [PubMed]

55.

Bankir L, Bochud M, Maillard M, Bovet P, Gabriel A, Burnier M. Nighttime blood pressure and nocturnal dipping are associated with daytime urinary sodium excretion in African subjects. Hypertension. 2008;51:891–8. [DOI] [PubMed]

56.

Birkenhager AM, van den Meiracker AH. Causes and consequences of a non-dipping blood pressure profile. Neth J Med. 2007;65:127–31. [PubMed]

57.

Bouhanick B, Bongard V, Amar J, Bousquel S, Chamontin B. Prognostic value of nocturnal blood pressure and reverse-dipping status on the occurrence of cardiovascular events in hypertensive diabetic patients. Diabetes Metab. 2008;34:560–7. [DOI] [PubMed]

58.

Hassan MO, Jaju D, Albarwani S, Al-Yahyaee S, Al-Hadabi S, Lopez-Alvarenga JC, et al. Non-dipping blood pressure in the metabolic syndrome among Arabs of the Oman family study. Obesity (Silver Spring). 2007;15:2445–53. [DOI] [PubMed]

59.

Kastarinen H, Vasunta RL, Ukkola O, Kesaniemi YA. Glomerular filtration rate is related to dipping pattern in ambulatory blood pressure monitoring--a cross-sectional population-based study. J Hum Hypertens. 2010;24:247–53. [DOI] [PubMed]

60.

Mellman TA, Brown DD, Jenifer ES, Hipolito MM, Randall OS. Posttraumatic stress disorder and nocturnal blood pressure dipping in young adult African Americans. Psychosom Med. 2009;71:627–30. [DOI] [PubMed]

61.

Nagai M, Hoshide S, Ishikawa J, Shimada K, Kario K. Ambulatory blood pressure as an independent determinant of brain atrophy and cognitive function in elderly hypertension. J Hypertens. 2008;26:1636–41. [DOI] [PubMed]

62.

Hajjar I, Zhao P, Alsop D, Abduljalil A, Selim M, Novak P, et al. Association of blood pressure elevation and nocturnal dipping with brain atrophy, perfusion and functional measures in stroke and nonstroke individuals. Am J Hypertens. 2010;23:17–23. [DOI] [PubMed] [PMC]

63.

Hajjar I, Selim M, Novak P, Novak V. The relationship between nighttime dipping in blood pressure and cerebral hemodynamics in nonstroke patients. J Clin Hypertens (Greenwich). 2007;9:929–36. [DOI] [PubMed]

64.

Carrington MJ, Trinder J. Blood pressure and heart rate during continuous experimental sleep fragmentation in healthy adults. Sleep. 2008;31:1701–12. [DOI] [PubMed] [PMC]

65.

Davies RJ, Belt PJ, Roberts SJ, Ali NJ, Stradling JR. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol. 1993;74:1123–30. [DOI] [PubMed]

66.

Morrell MJ, Finn L, Kim H, Peppard PE, Badr MS, Young T. Sleep fragmentation, awake blood pressure, and sleep-disordered breathing in a population-based study. Am J Respir Crit Care Med. 2000;162:2091–6. [DOI] [PubMed]

67.

Ogawa Y, Kanbayashi T, Saito Y, Takahashi Y, Kitajima T, Takahashi K, et al. Total sleep deprivation elevates blood pressure through arterial baroreflex resetting: a study with microneurographic technique. Sleep. 2003;26:986–9. [DOI] [PubMed]

68.

Alchanatis M, Deligiorgis N, Zias N, Amfilochiou A, Gotsis E, Karakatsani A, et al. Frontal brain lobe impairment in obstructive sleep apnoea: a proton MR spectroscopy study. Eur Respir J. 2004;24:980–6. [DOI] [PubMed]

69.

O’Donoghue FJ, Wellard RM, Rochford PD, Dawson A, Barnes M, Ruehland WR, et al. Magnetic resonance spectroscopy and neurocognitive dysfunction in obstructive sleep apnea before and after CPAP treatment. Sleep. 2012;35:41–8. [DOI] [PubMed] [PMC]

70.

Row BW, Liu R, Xu W, Kheirandish L, Gozal D. Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med. 2003;167:1548–53. [DOI] [PubMed]

71.

Xu W, Chi L, Row BW, Xu R, Ke Y, Xu B, et al. Increased oxidative stress is associated with chronic intermittent hypoxia-mediated brain cortical neuronal cell apoptosis in a mouse model of sleep apnea. Neuroscience. 2004;126:313–23. [DOI] [PubMed]

72.

Li RC, Row BW, Kheirandish L, Brittian KR, Gozal E, Guo SZ, et al. Nitric oxide synthase and intermittent hypoxia-induced spatial learning deficits in the rat. Neurobiol Dis. 2004;17:44–53. [DOI] [PubMed]

73.

Nair D, Dayyat EA, Zhang SX, Wang Y, Gozal D. Intermittent hypoxia-induced cognitive deficits are mediated by NADPH oxidase activity in a murine model of sleep apnea. PLoS One. 2011;6:e19847. [DOI] [PubMed] [PMC]

74.

Thomas RJ, Weiss MD, Mietus JE, Peng CK, Goldberger AL, Gottlieb DJ. Prevalent hypertension and stroke in the Sleep Heart Health Study: association with an ECG-derived spectrographic marker of cardiopulmonary coupling. Sleep. 2009;32:897–904. [PubMed] [PMC]

75.

Silva GE, An MW, Goodwin JL, Shahar E, Redline S, Resnick H, et al. Longitudinal evaluation of sleep-disordered breathing and sleep symptoms with change in quality of life: the Sleep Heart Health Study (SHHS). Sleep. 2009;32:1049–57. [DOI] [PubMed] [PMC]

76.

Shen X, Adams MJ, Ritakari TE, Cox SR, McIntosh AM, Whalley HC. White matter microstructure and its relation to longitudinal measures of depressive symptoms in mid- and late life. Biol Psychiatry. 2019;86:759–68. [DOI] [PubMed] [PMC]

77.

Beck D, de Lange AG, Maximov II, Richard G, Andreassen OA, Nordvik JE, et al. White matter microstructure across the adult lifespan: a mixed longitudinal and cross-sectional study using advanced diffusion models and brain-age prediction. Neuroimage. 2020;224:117441. [DOI] [PubMed]

78.

Wang YL, Chen W, Cai WJ, Hu H, Xu W, Wang ZT, et al. Associations of white matter hyperintensities with cognitive decline: a longitudinal study. J Alzheimers Dis. 2020;73:759–68. [DOI] [PubMed]