Skip to main content

Advertisement

SpringerLink
Log in

Dementia Risk in Posttraumatic Stress Disorder: the Relevance of Sleep-Related Abnormalities in Brain Structure, Amyloid, and Inflammation

  • Disaster Psychiatry: Trauma, PTSD, and Related Disorders (MJ Friedman, Section Editor)
  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Posttraumatic stress disorder (PTSD) is associated with increased risk for dementia, yet mechanisms are poorly understood.

Recent Findings

Recent literature suggests several potential mechanisms by which sleep impairments might contribute to the increased risk of dementia observed in PTSD. First, molecular, animal, and imaging studies indicate that sleep problems lead to cellular damage in brain structures crucial to learning and memory. Second, recent studies have shown that lack of sleep might precipitate the accumulation of harmful amyloid proteins. Finally, sleep and PTSD are associated with elevated inflammation, which, in turn, is associated with dementia, possibly via cytokine-mediated neural toxicity and reduced neurogenesis.

Summary

A better understanding of these mechanisms may yield novel treatment approaches to reduce neurodegeneration in PTSD. The authors emphasize the importance of including sleep data in studies of PTSD and cognition and identify next steps.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Yaffe K, Vittinghoff E, Lindquist K, Barnes D, Covinsky KE, Neylan T, et al. Posttraumatic stress disorder and risk of dementia among US VeteransPTSD and dementia in US veterans. Arch Gen Psychiatry. 2010;67:608–13.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Qureshi SU, Kimbrell T, Pyne JM, Magruder KM, Hudson TJ, Petersen NJ, et al. Greater prevalence and incidence of dementia in older veterans with posttraumatic stress disorder. J Am Geriatr Soc. 2010;58:1627–33.

    Article  PubMed  Google Scholar 

  3. Sha S, Hou C, Viskontas IV, Miller BL. Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases? Nat Clin Pract Neurol. 2006;2:658–65.

    Article  PubMed  Google Scholar 

  4. Sperling W, Kreil SK, Biermann T. Posttraumatic stress disorder and dementia in Holocaust survivors. J Nerv Ment Dis. 2011;199:196–8.

    Article  PubMed  Google Scholar 

  5. Dallam DL, Mellman TA, Bhatnagar A, Nguyen S, Kurukumbi M. Trauma reenactments in aging veterans with dementia. J Am Geriatr Soc. 2011;59:766–8.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Merlino G, Piani A, Gigli GL, Cancelli I, Rinaldi A, Baroselli A, et al. Daytime sleepiness is associated with dementia and cognitive decline in older Italian adults: a population-based study. Sleep Med. 2010;11:372–7.

    Article  CAS  PubMed  Google Scholar 

  7. Osorio RS, Pirraglia E, Agüera-Ortiz LF, et al. Greater risk of Alzheimer's disease in older adults with insomnia. J Am Geriatr Soc. 2011;59:559–62.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Foley D, Monjan A, Masaki K, Ross W, Havlik R, White L, et al. Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc. 2001;49:1628–32.

    Article  CAS  PubMed  Google Scholar 

  9. Blackwell T, Yaffe K, Ancoli-Israel S, Redline S, Ensrud KE, Stefanick ML, et al. Association of sleep characteristics and cognition in older community-dwelling men: the MrOS sleep study. Sleep. 2011;34:1347–56.

    PubMed  PubMed Central  Google Scholar 

  10. • Blackwell T, Yaffe K, Laffan A, Ancoli-Israel S, Redline S, Ensrud KE, et al., Osteoporotic Fractures in Men (MrOS) Study Group. Associations of objectively and subjectively measured sleep quality with subsequent cognitive decline in older community-dwelling men: the MrOS sleep study. Sleep. 2014;37:655–63. In this study of 2,822 older men, poor sleep quality and quantify, measured subjectively and objectively using wrist actigraphy, predicted subsequent cognitive decline.

  11. Tranah GJ, Blackwell T, Stone KL, et al. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol. 2011;70:722–32.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ju Y-ES, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology-a bidirectional relationship. Nat Publ Group. 2013;10:115–9.

    Google Scholar 

  13. Ju Y-E, Duntley S, Fagan A, Morris J, Holtzman D. Sleep disruption and risk of preclinical Alzheimer disease (P01.081). Neurology. 2012;78:P01.081.

    Article  Google Scholar 

  14. Germain A. Sleep disturbances as the hallmark of PTSD: where are we now? Am J Psychiatr. 2013;170:372–82.

    Article  PubMed  PubMed Central  Google Scholar 

  15. American Psychiatric Association (2014) Trauma- and stressor-related disorders. In: Fifth edition. American Psychiatric Association doi: https://doi.org/10.1176/appi.books.9780890425596.dsm07

  16. Lamarche LJ, De Koninck J. Sleep disturbance in adults with posttraumatic stress disorder: a review. J Clin Psychiatry. 2007;68:1257–70.

    Article  PubMed  Google Scholar 

  17. Maker MJ, Rego SA, Asnis GM. Sleep disturbances in patients with post-traumatic stress disorder. CNS Drugs. 2006;20:567–90.

    Article  Google Scholar 

  18. Babson K, Feldner M, Badour C, Trainor C, Blumenthal H, Sachs-Ericsson N, et al. Posttraumatic stress and sleep: differential relations across types of symptoms and sleep problems. J Anxiety Disord. 2011;25:706–13.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mellman TA, Kulick-Bell R, Ashlock LE, Nolan B. Sleep events among veterans with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:110–5.

    Article  CAS  PubMed  Google Scholar 

  20. Neylan TC, Marmar CR, Metzler TJ, Weiss DS, Zatzick DF, Delucchi KL, et al. Sleep disturbances in the Vietnam generation: findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry. 1998;155:929–33.

    Article  CAS  PubMed  Google Scholar 

  21. Inman DJ, Silver SM, Doghramji K. Sleep disturbance in post-traumatic stress disorder: a comparison with non-PTSD insomnia. J Trauma Stress. 1990;3:429–37.

    Article  Google Scholar 

  22. Pigeon WR, Campbell CE, Possemato K, Ouimette P. Longitudinal relationships of insomnia, nightmares, and PTSD severity in recent combat veterans. J Psychosom Res. 2013;75:546–50.

    Article  PubMed  Google Scholar 

  23. Breslau N, Roth T, Burduvali E, Kapke A, Schultz L, Roehrs T. Sleep in lifetime posttraumatic stress disorder: a community-based polysomnographic study. Arch Gen Psychiatry. 2004;61:508–16.

    Article  PubMed  Google Scholar 

  24. Mohlenhoff BS, Chao LL, Buckley ST, Weiner MW, Neylan TC. Are hippocampal size differences in posttraumatic stress disorder mediated by sleep pathology? Alzheimers Dement. 2014;10:S146–54.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lavie P, Katz N, Pillar G, Zinger Y. Elevated awaking thresholds during sleep: characteristics of chronic war-related posttraumatic stress disorder patients. BPS. 1998;44:1060–5.

    CAS  Google Scholar 

  26. Keage HAD, Banks S, Yang KL, Morgan K, Brayne C, Matthews FE. What sleep characteristics predict cognitive decline in the elderly? Sleep Med. 2012;13:886–92.

    Article  PubMed  Google Scholar 

  27. Lim ASP, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep fragmentation and the risk of incident Alzheimer's disease and cognitive decline in older persons. Sleep. https://doi.org/10.5665/sleep.2802.

  28. Kobayashi I, Boarts JM, Delahanty DL. Polysomnographically measured sleep abnormalities in PTSD: a meta-analytic review. Psychophysiology. 2007;44:660–9.

    Article  PubMed  Google Scholar 

  29. Dow BM, Kelsoe JR, Gillin JC. Sleep and dreams in Vietnam PTSD and depression. BPS. 1996;39:42–50.

    CAS  Google Scholar 

  30. Fuller KH, Waters WF, Scott O. An investigation of slow-wave sleep processes in chronic PTSD patients. J Anxiety Disord. 1994;8:227–36.

    Article  Google Scholar 

  31. Germain A, Nielsen TA. Sleep pathophysiology in posttraumatic stress disorder and idiopathic nightmare sufferers. Biol Psychiatry. 2003;54:1092–8.

    Article  PubMed  Google Scholar 

  32. Mellman TA, Kobayashi I, Lavela J, Wilson B, Hall Brown TSA. Relationship between REM sleep measures and the duration of posttraumatic stress disorder in a young adult urban minority population. Sleep. https://doi.org/10.5665/sleep.3922.

  33. Mellman TA, Bustamante V, Fins AI, Pigeon WR, Nolan B. REM sleep and the early development of posttraumatic stress disorder. Am J Psychiatry. 2002;159:1696–701.

    Article  PubMed  Google Scholar 

  34. Ross RJ, Ball WA, Dinges DF, Kribbs NB, Morrison AR, Silver SM, et al. Motor dysfunction during sleep in posttraumatic stress disorder. Sleep. 1994;17:723–32.

    Article  CAS  PubMed  Google Scholar 

  35. Gehrman P, Seelig AD, Jacobson IG, Boyko EJ, Hooper TI, Gackstetter GD, et al. Predeployment sleep duration and insomnia symptoms as risk factors for new-onset mental health disorders following military deployment. Sleep. https://doi.org/10.5665/sleep.2798.

  36. McEwen BS, Magarinos AM. Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci. 1997;821:271–84.

    Article  CAS  PubMed  Google Scholar 

  37. Apfel BA, Ross J, Hlavin J, Meyerhoff DJ, Metzler TJ, Marmar CR, et al. Hippocampal volume differences in Gulf War veterans with current versus lifetime posttraumatic stress disorder symptoms. Biol Psychiatry. 2011;69:541–8.

    Article  PubMed  Google Scholar 

  38. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995;152:973–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Woon FL, Sood S, Hedges DW. Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysis. Prog Neuro-Psychopharmacol Biol Psychiatry. 2010;34:1181–8.

    Article  Google Scholar 

  40. Chao L, Weiner M, Neylan T. Regional cerebral volumes in veterans with current versus remitted posttraumatic stress disorder. Psychiatry Res Neuroimaging. 2013;213:193–201.

    Article  PubMed  Google Scholar 

  41. Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, et al. Decreased hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder. Biol Psychiatry. 2001;50:952–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schuff N, Neylan TC, Fox-Bosetti S, Lenoci M, Samuelson KW, Studholme C, et al. Abnormal N-acetylaspartate in hippocampus and anterior cingulate in posttraumatic stress disorder. Psychiatry Res. 2008;162:147–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, et al. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry. 2001;158:1248–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fennema-Notestine C, Stein MB, Kennedy CM, Archibald SL, Jernigan TL. Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder. BPS. 2002;52:1089–101.

    Google Scholar 

  45. Karl A, Schaefer M, Malta LS, Dörfel D, Rohleder N, Werner A. A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev. 2006;30:1004–31.

    Article  PubMed  Google Scholar 

  46. Acheson DT, Gresack JE, Risbrough VB. Hippocampal dysfunction effects on context memory: possible etiology for posttraumatic stress disorder. Neuropharmacology. 2012;62:674–85.

    Article  CAS  PubMed  Google Scholar 

  47. Wang Z, Neylan TC, Mueller SG, Lenoci M, Truran D, Marmar CR, et al. Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder. Arch Gen Psychiatry. 2010;67:296–303.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Admon R, Milad MR, Hendler T. A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends Cogn Sci. 2013;17:337–47.

    Article  PubMed  Google Scholar 

  49. Sapolsky RM. Chickens, eggs and hippocampal atrophy. Nat Neurosci. 2002;5:1111–3.

    Article  CAS  PubMed  Google Scholar 

  50. Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP, et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci. 2002;5:1242–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cardenas VA, Samuelson K, Lenoci M, Studholme C, Neylan TC, Marmar CR, et al. Changes in brain anatomy during the course of posttraumatic stress disorder. Psychiatry Res. 2011;193:93–100.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Novati A, Hulshof HJ, Granic I, Meerlo P. Chronic partial sleep deprivation reduces brain sensitivity to glutamate N-methyl-D-aspartate receptor-mediated neurotoxicity. J Sleep Res. 2012;21:3–9.

    Article  PubMed  Google Scholar 

  53. Riemann D, Voderholzer U, Spiegelhalder K, Hornyak M, Buysse DJ, Nissen C, et al. Chronic insomnia and MRI-measured hippocampal volumes: a pilot study. Sleep. 2007;30:955–8.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Taki Y, Hashizume H, Thyreau B, et al. Sleep duration during weekdays affects hippocampal gray matter volume in healthy children. NeuroImage. 2012;60:471–5.

    Article  PubMed  Google Scholar 

  55. Noh HJ, Joo EY, Kim ST, Yoon SM, Koo DL, Kim D, et al. The relationship between hippocampal volume and cognition in patients with chronic primary insomnia. J Clin Neurol. 2012;8:130–8.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Winkelman JW, Benson KL, Buxton OM, Lyoo IK, Yoon S, O’Connor S, et al. Lack of hippocampal volume differences in primary insomnia and good sleeper controls: an MRI volumetric study at 3 Tesla. Sleep Med. 2010;11:576–82.

    Article  PubMed  Google Scholar 

  57. Conrad CD. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev Neurosci. 2008;19:395–411.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Neylan TC, Mueller SG, Wang Z, Metzler TJ, Lenoci M, Truran D, et al. Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield. BPS. 2010;68:494–6.

    Google Scholar 

  59. Chao LL, Mohlenhoff BS, Weiner MW, Neylan TC. Associations between subjective sleep quality and brain volume in gulf war veterans. Sleep. https://doi.org/10.5665/sleep.3472.

  60. Zorumski CF, Izumi Y. NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. Neurosci Biobehav Rev. 2012;36:989–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Davis CJ, Meighan PC, Taishi P, Krueger JM, Harding JW, Wright JW. REM sleep deprivation attenuates actin-binding protein cortactin: a link between sleep and hippocampal plasticity. Neurosci Lett. 2006;400:191–6.

    Article  CAS  PubMed  Google Scholar 

  62. Hagewoud R, Havekes R, Novati A, Kaijser JN, Van der Zee EA, Meerlo P. Sleep deprivation impairs spatial working memory and reduces hippocampal AMPA receptor phosphorylation. J Sleep Res. 2010;19:280–8.

    Article  PubMed  Google Scholar 

  63. Guzman-Marin R, Bashir T, Suntsova N, Szymusiak R, McGinty D. Hippocampal neurogenesis is reduced by sleep fragmentation in the adult rat. Neuroscience. 2007;148:325–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Guzman-Marin R, Suntsova N, Methippara M, Greiffenstein R, Szymusiak R, McGinty D. Sleep deprivation suppresses neurogenesis in the adult hippocampus of rats. Eur J Neurosci. 2005;22:2111–6.

    Article  PubMed  Google Scholar 

  65. Guzman-Marin R, Suntsova N, Bashir T, Nienhuis R, Szymusiak R, McGinty D. Rapid eye movement sleep deprivation contributes to reduction of neurogenesis in the hippocampal dentate gyrus of the adult rat. Sleep. 2008;31:167–75.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hairston IS. Sleep restriction suppresses neurogenesis induced by hippocampus-dependent learning. J Neurophysiol. 2005;94:4224–33.

    Article  PubMed  Google Scholar 

  67. Chang H-M, Liao W-C, Sheu J-N, Chang C-C, Lan C-T, Mai F-D. Sleep deprivation impairs Ca2+ expression in the hippocampus: ionic imaging analysis for cognitive deficiency with TOF-SIMS. Microsc Microanal. 2012;18:425–35.

    Article  CAS  PubMed  Google Scholar 

  68. de Souza L, Smaili SS, Ureshino RP, Sinigaglia-Coimbra R, Andersen ML, Lopes GS, et al. Effect of chronic sleep restriction and aging on calcium signaling and apoptosis in the hippocampus of young and aged animals. Prog Neuro-Psychopharmacol Biol Psychiatry. 2012;39:23–30.

    Article  CAS  Google Scholar 

  69. Chen C, Hardy M, Zhang J, LaHoste GJ, Bazan NG. Altered NMDA receptor trafficking contributes to sleep deprivation-induced hippocampal synaptic and cognitive impairments. Biochem Biophys Res Commun. 2006;340:435–40.

    Article  CAS  PubMed  Google Scholar 

  70. Davis CJ, Harding JW, Wright JW. REM sleep deprivation-induced deficits in the latency-to-peak induction and maintenance of long-term potentiation within the CA1 region of the hippocampus. Brain Res. 2003;973:293–7.

    Article  CAS  PubMed  Google Scholar 

  71. Kim EY, Mahmoud GS, Grover LM. REM sleep deprivation inhibits LTP in vivo in area CA1 of rat hippocampus. Neurosci Lett. 2005;388:163–7.

    Article  CAS  PubMed  Google Scholar 

  72. McDermott CM, LaHoste GJ, Chen C, Musto A, Bazan NG, Magee JC. Sleep deprivation causes behavioral, synaptic, and membrane excitability alterations in hippocampal neurons. J Neurosci. 2003;23:9687–95.

    CAS  PubMed  Google Scholar 

  73. Sportiche N, Suntsova N, Methippara M, Bashir T, Mitrani B, Szymusiak R, et al. Sustained sleep fragmentation results in delayed changes in hippocampal-dependent cognitive function associated with reduced dentate gyrus neurogenesis. Neuroscience. 2010;170:247–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Süer C, Dolu N, Artis AS, Sahin L, Yilmaz A, Cetin A. The effects of long-term sleep deprivation on the long-term potentiation in the dentate gyrus and brain oxidation status in rats. Neurosci Res. 2011;70:71–7.

    Article  PubMed  CAS  Google Scholar 

  75. Tartar JL, Ward CP, McKenna JT, Thakkar M, Arrigoni E, McCarley RW, et al. Hippocampal synaptic plasticity and spatial learning are impaired in a rat model of sleep fragmentation. Eur J Neurosci. 2006;23:2739–48.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Eichenbaum H. What hm taught us. J Cogn Neurosci. 2013;25:14–21.

    Article  PubMed  Google Scholar 

  77. Fulda S, Schulz H. Cognitive dysfunction in sleep disorders. Sleep Med Rev. 2001;5:423–45.

    Article  CAS  PubMed  Google Scholar 

  78. Brownlow JA, Hall Brown TS, Mellman TA. Relationships of posttraumatic stress symptoms and sleep measures to cognitive performance in young-adult African Americans. J Trauma Stress. 2014;27:217–23.

    Article  PubMed  Google Scholar 

  79. Brewin CR, Kleiner JS, Vasterling JJ, Field AP. Memory for emotionally neutral information in posttraumatic stress disorder: a meta-analytic investigation. J Abnorm Psychol. 2007;116:448–63.

    Article  PubMed  Google Scholar 

  80. Johnsen GE, Kanagaratnam P, Asbjørnsen AE. Memory impairments in posttraumatic stress disorder are related to depression. J Anxiety Disord. 2008;22:464–74.

    Article  PubMed  Google Scholar 

  81. Burriss L, Ayers E, Ginsberg J, Powell DA. Learning and memory impairment in PTSD: relationship to depression. Depress Anxiety. 2008;25:149–57.

    Article  PubMed  Google Scholar 

  82. Scarmeas N, Stern Y. Cognitive reserve: implications for diagnosis and prevention of Alzheimer's disease. Curr Neurol Neurosci Rep. 2004;4:374–80.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712.

    Article  CAS  PubMed  Google Scholar 

  84. Buée L, Troquier L, Burnouf S, et al. From tau phosphorylation to tau aggregation: what about neuronal death? Biochem Soc Trans. 2010;38:967.

    Article  PubMed  CAS  Google Scholar 

  85. Huang Y, Potter R, Sigurdson W, et al. Effects of age and amyloid deposition on Abeta dynamics in the human central nervous system. Arch Neurol. 2012;69:51–8.

    Article  PubMed  Google Scholar 

  86. Molano JRV, Roe CM, Ju Y-ES. The interaction of sleep and amyloid deposition on cognitive performance. J Sleep Res. 2016;26:288–92.

    Article  PubMed  Google Scholar 

  87. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373–7.

    Article  CAS  PubMed  Google Scholar 

  88. Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013; https://doi.org/10.1001/jamaneurol.2013.4258.

  89. Weiner MW, Veitch DP, Hayes J, et al. Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer“s disease in veterans, using the Alzheimer”s disease neuroimaging initiative. Alzheimers Dement. 2014;10:S226–35.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sprecher KE, Koscik RL, Carlsson CM, et al. Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017; https://doi.org/10.1212/WNL.0000000000004171–9.

  91. Donovan AO, Neylan TC, Metzler T, Cohen BE. Lifetime exposure to traumatic psychological stress is associated with elevated inflammation in the Heart and Soul Study. Brain Behav Immun. 2012;26:642–9.

    Article  CAS  Google Scholar 

  92. Hoge EA, Brandstetter K, Moshier S, Pollack MH, Wong KK, Simon NM. Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depress Anxiety. 2009;26:447–55.

    Article  CAS  PubMed  Google Scholar 

  93. Spitzer C, Barnow S, Völzke H, Wallaschofski H, John U, Freyberger HJ, et al. Association of posttraumatic stress disorder with low-grade elevation of C-reactive protein: evidence from the general population. J Psychiatr Res. 2010;44:15–21.

    Article  PubMed  Google Scholar 

  94. Pace TWW, Heim CM. A short review on the psychoneuroimmunology of posttraumatic stress disorder: from risk factors to medical comorbidities. Brain Behav Immun. 2011;25:6–13.

    Article  CAS  PubMed  Google Scholar 

  95. Baker DG, Nievergelt CM, O'Connor DT. Biomarkers of PTSD: neuropeptides and immune signaling. Neuropharmacology. 2012;62:663–73.

    Article  CAS  PubMed  Google Scholar 

  96. O’Donovan A, Sun B, Cole S, Rempel H, Lenoci M, Pulliam L, et al. Transcriptional control of monocyte gene expression in post-traumatic stress disorder. Dis Markers. 2011;30:123–32.

    Article  PubMed  PubMed Central  Google Scholar 

  97. • O’Donovan A, Chao LL, Paulson J, Samuelson KW, Shigenaga JK, Grunfeld C, et al. Altered inflammatory activity associated with reduced hippocampal volume and more severe posttraumatic stress symptoms in Gulf War veterans. Psychoneuroendocrinology. 2015;51:557–66. Greater PTSD symptom burden was associated in this study with higher levels of serum tumor necrosis factor, which, in turn, was associated with smaller hippocampal volumes.

    Article  PubMed  Google Scholar 

  98. McCanlies EC, Araia SK, Joseph PN, Mnatsakanova A, Andrew ME, Burchfiel CM, et al. C-reactive protein, Interleukin-6, and posttraumatic stress disorder symptomology in urban police officers. Cytokine. 2011;55:74–8.

    Article  CAS  PubMed  Google Scholar 

  99. Söndergaard HP, Hansson L-O, Theorell T. The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder. Clin Chim Acta. 2004;342:93–8.

    Article  PubMed  CAS  Google Scholar 

  100. •• Passos IC, Vasconcelos-Moreno MP, Costa LG. Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression. Lancet Psychiatry. 2015;2:1002–12. https://doi.org/10.1016/S2215-0366(15)00309-0. This thorough and thoughtful meta-analysis and meta-regression included 20 studies of inflammatory markers in PTSD and found that PTSD was associated with higher levels of IL-6, IL-1 and interferon. Additionally, TNF- α was higher in subjects with PTSD only in a subgroup analysis of patients who were not on psychotropic medications, IL-6 was associated with illness severity but not with illness duration and Illness duration was associated with IL-1 levels. This review includes tables outlining the literature on inflammation and PTSD.

  101. Eraly SA, Nievergelt CM, Maihofer AX, Barkauskas DA, Biswas N, Agorastos A, et al. Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry. 2014;71:423–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen J, Song Y, Yang J, Zhang Y, Zhao P, Zhu X-J, et al. The contribution of TNF-α in the amygdala to anxiety in mice with persistent inflammatory pain. Neurosci Lett. 2013;541:275–80.

    Article  CAS  PubMed  Google Scholar 

  103. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Engler H, Doenlen R, Engler A, Riether C, Prager G, Niemi M-B, et al. Acute amygdaloid response to systemic inflammation. Brain Behav Immun. 2011;25:1384–92.

    Article  CAS  PubMed  Google Scholar 

  105. Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI. Inflammation selectively enhances amygdala activity to socially threatening images. NeuroImage. 2012;59:3222–6.

    Article  PubMed  Google Scholar 

  106. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression. JAMA Psychiatry. 2013;70:31–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298:1685–7.

    Article  CAS  PubMed  Google Scholar 

  108. Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104:1319–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Dekaris D, Sabioncello A, Mažuran R, Rabatić S. Multiple changes of immunologic parameters in prisoners of war: assessments after release from a camp in manjača, bosnia. JAMA. 1993;270:595–9.

    Article  CAS  PubMed  Google Scholar 

  110. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007;21:901–12.

    Article  CAS  PubMed  Google Scholar 

  111. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun. 2011;16:622–53.

    Article  Google Scholar 

  112. Donovan AO, Ahmadian AJ, Neylan TC, Pacult MA, Edmondson D, Cohen BE. Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study. Brain Behav Immun. 2017;60:198–205.

    Article  Google Scholar 

  113. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, et al. Inflammatory proteins in plasma and the risk of dementia: the Rotterdam study. Arch Neurol. 2004;61:668–72.

    Article  PubMed  Google Scholar 

  114. Tan ZS, Beiser AS, Vasan RS, Roubenoff R, Dinarello CA, Harris TB, et al. Inflammatory markers and the risk of Alzheimer disease the Framingham study. Neurology. 2007;68:1902–8.

    Article  CAS  PubMed  Google Scholar 

  115. McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging. 2007;28:639–47.

    Article  CAS  PubMed  Google Scholar 

  116. Gagne JJ, Power MC. Anti-inflammatory drugs and risk of Parkinson disease: a meta-analysis. Neurology. 2010;74:995–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tobinick E. Deciphering the physiology underlying the rapid clinical effects of perispinal etanercept in Alzheimer's disease. Curr Alzheimer Res. 2012;9:99–109.

    Article  CAS  PubMed  Google Scholar 

  118. Zipp F, Aktas O. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci. 2006;29:518–27.

    Article  CAS  PubMed  Google Scholar 

  119. Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7:161–7.

    Article  CAS  PubMed  Google Scholar 

  120. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31.

    Article  CAS  PubMed  Google Scholar 

  121. Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun. 2011;25:181–213.

    Article  CAS  PubMed  Google Scholar 

  122. •• Marsland AL, Gianaros PJ, Kuan DCH, Sheu LK, Krajina K, Manuck SB. Brain morphology links systemic inflammation to cognitive function in midlife adults. Brain Behav Immun. 2015;48:195–204. While not directly related to PTSD, this study of 408 subjects links peripheral inflammation to poorer performance in multiple cognitive domains as well as smaller volumes of brain structures crucial to learning and memory.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Leonard BE. Inflammation, depression and dementia: are they connected? Neurochem Res. 2007;32:1749–56.

    Article  CAS  PubMed  Google Scholar 

  124. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia aging study. Ann Neurol. 2002;52:168–74.

    Article  PubMed  Google Scholar 

  125. Rogers J, Griffin WST. Inflammatory mechanisms of Alzheimer's disease. In: Wood P, editor. Neuroinflammation: mechanisms and management. New York: Springer Science+Business Media; 1998. p. 177–93.

    Chapter  Google Scholar 

  126. Imeri L, Opp MR. How (and why) the immune system makes us sleep. Nat Rev Neurosci. 2009;10:199–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Irwin M. Effects of sleep and sleep loss on immunity and cytokines. Brain Behav Immun. 2002;16:503–12.

    Article  CAS  PubMed  Google Scholar 

  128. Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med. 2006;166:1756–62.

    Article  CAS  PubMed  Google Scholar 

  129. Irwin MR, Wang M, Ribeiro D, Cho HJ, Olmstead R, Breen EC, et al. Sleep loss activates cellular inflammatory signaling. Biol Psychiatry. 2008;64:538–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010;24:775–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Barr T, Livingston W, Guardado P, Baxter T, Mysliwiec V, Gill J. Chapter 8 military personnel with traumatic brain injuries and insomnia have reductions in PTSD and improved perceived health following sleep restoration: a relationship moderated by inflammation. Annu Rev Nurs Res. 2015;33:249–66.

    Article  PubMed  Google Scholar 

  132. Fu S, McFall M, Saxon A, Beckham J, Carmody T, Baker D, et al. Post-traumatic stress disorder and smoking: a systematic review. Nicotine Tob Res. 2007;9:1071–84.

    Article  PubMed  Google Scholar 

  133. Kofoed L, Friedman MJ, Peck R. Alcoholism and drug abuse in patients with PTSD. Psychiatry Q. 1993;64:151–71.

    Article  CAS  Google Scholar 

  134. Williams SG, Collen J, Orr N, Holley AB, Lettieri CJ. Sleep disorders in combat-related PTSD. Sleep Breath. 2014;19:175–82.

    Article  PubMed  Google Scholar 

  135. Jaoude P, Vermont LN, Porhomayon J, El-Solh AA. Sleep-disordered breathing in patients with post-traumatic stress disorder. Ann ATS. 2015;12:259–68.

    Article  Google Scholar 

  136. O'Hara R, Luzon A, Hubbard J, Zeitzer JM. Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: mechanism for cognitive dysfunction and development of dementia. JRRD. 2009;46:837.

    Article  Google Scholar 

  137. van Liempt S. Sleep disturbances and PTSD: a perpetual circle? Eur J Psychotraumatol. 2012;3:291.

    Google Scholar 

  138. Zanigni S, Calandra-Buonaura G, Grimaldi D, Cortelli P. REM behaviour disorder and neurodegenerative diseases. Sleep Med. 2011;12:S54–8.

    Article  PubMed  Google Scholar 

  139. Gagnon J-F, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 2006;5:424–32.

    Article  PubMed  Google Scholar 

  140. Boeve BF, Saper CB. REM sleep behavior disorder: a possible early marker for synucleinopathies. Neurology. 2006;66:796–7.

    Article  PubMed  Google Scholar 

  141. Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J. Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology. 2006;66:845–51.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Psychiatry, University of California, San Francisco, CA, USA

    Brian S. Mohlenhoff, Aoife O’Donovan, Michael W. Weiner & Thomas C. Neylan

  2. Center for Imaging of Neurodegenerative Disease, Veterans Administration Medical Center, 4150 Clement Street (116P), San Francisco, CA, 94121, USA

    Brian S. Mohlenhoff, Michael W. Weiner & Thomas C. Neylan

  3. Mental Health Service, Department of Veterans Affairs Medical Center, San Francisco, CA, USA

    Brian S. Mohlenhoff & Aoife O’Donovan

  4. Departments of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA

    Michael W. Weiner

Authors
  1. Brian S. Mohlenhoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aoife O’Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael W. Weiner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas C. Neylan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian S. Mohlenhoff.

Ethics declarations

Conflict of Interest

Thomas C. Neylan declares no conflict of interest.

Brian S. Mohlenhoff received salary support from the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment at the San Francisco Veterans Affairs Medical Center and the Department of Veterans Affairs Sierra-Pacific Region Mental Illness Research, Education and Clinical Center (MIRECC).

Aoife O’Donovan received salary support from Society in Science – The Branco Weiss Fellowship and a NIMH Career Development Award (K01-MH109871). This study was supported by the NIH/NIA/National Institute of Mental Health (BSM: R25MH060482; TCN: 5R01MH073978–04, 5R34MH077667–03, 1R56MH107042-01A1; MWW: R01AG10897, 2U01AG024904, 1P41 EB015904, P01 AG19724, R01 AG032306, R01A G03879) and by funding from the US Veterans Health Administration for the Mental Illness Research, Education and Clinical Center, VISN 21 and grant DAMD17–01–1-0764.

Michael W. Weiner has served on the Scientific Advisory Boards for Pfizer, BOLT International, Neurotrope Bioscience, and Eli Lilly. He has provided consulting to Synarc, Pfizer, Janssen, KLJ Associates, Easton Associates, Harvard University, University of California, Los Angeles (UCLA), Alzheimer’s Drug Discovery Foundation (ADDF), Avid Radiopharmaceuticals, Clearview Healthcare Partners, Perceptive Informatics, Smartfish AS, Decision Resources, Inc., Araclon, Merck, Defined Health, and Genentech. The following entities have provided funding for travel: Pfizer, Paul Sabatier University, MCI Group France, Travel eDreams, Inc., Neuroscience School of Advanced Studies (NSAS), Danone Trading, BV, CTAD Ant Congres, Kenes, Intl., ADRC, UCLA, UCSD, Sanofi-Aventis Groupe, University Center Hospital, Toulouse, Araclon, AC Immune, Eli Lilly, New York Academy of Sciences (NYAS), and National Brain Research Center, India for Johns Hopkins Medicine. He served on the Editorial Boards for Alzheimer’s & Dementia and MRI. He received honoraria from Pfizer, Tohoku University, and Danone Trading, BV. He received research support from Merck, Avid, the Veterans Administration (VA) and Department of Defense (DOD). Dr. Weiner additionally received support for his work from the following grants: W81XWH-13-1-0259, W81XWH-12-2-0012, ADNI 2–12-233,036, 20,110,506 and R01 MH098062–01 from the following sources; DOD, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Disaster Psychiatry: Trauma, PTSD, and Related Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mohlenhoff, B.S., O’Donovan, A., Weiner, M.W. et al. Dementia Risk in Posttraumatic Stress Disorder: the Relevance of Sleep-Related Abnormalities in Brain Structure, Amyloid, and Inflammation. Curr Psychiatry Rep 19, 89 (2017). https://doi.org/10.1007/s11920-017-0835-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11920-017-0835-1

Keywords

Search

Navigation