Acta Neuropathologica

, Volume 129, Issue 4, pp 493–509 | Cite as

One is the deadliest number: the detrimental effects of social isolation on cerebrovascular diseases and cognition

  • Brett Friedler
  • Joshua Crapser
  • Louise McCullough


The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer’s disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.


Social isolation HPA axis SNS Inflammation Vascular disease Neurological disease 



Financial support for B.F. and J.C. generously provided by NIH/NINDS Grant Psychosocial Stress and Behavioral Response to Stroke (5R01NS077769) as well as NIH/NINDS Grant Chromosomal and Hormonal Contributions to Sex Differences in Ischemic Stroke (5R01NS055215). Financial support was also received in the form of an American Heart Association undergraduate student summer fellowship awarded to J.C.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    An C, Shi Y, Li P, Hu X, Gan Y, Stetler RA, Leak RK, Gao Y, Sun BL, Zheng P, Chen J (2014) Molecular dialogs between the ischemic brain and the peripheral immune system: dualistic roles in injury and repair. Prog Neurobiol 115:6–24. doi:10.1016/j.pneurobio.2013.12.002 PubMedGoogle Scholar
  2. 2.
    Aschbacher K, O’Donovan A, Wolkowitz OM, Dhabhar FS, Su Y, Epel E (2013) Good stress, bad stress and oxidative stress: insights from anticipatory cortisol reactivity. Psychoneuroendocrinology 38:1698–1708. doi:10.1016/j.psyneuen.2013.02.004 PubMedCentralPubMedGoogle Scholar
  3. 3.
    Barnes LL, Mendes de Leon CF, Wilson RS, Bienias JL, Evans DA (2004) Social resources and cognitive decline in a population of older African Americans and whites. Neurology 63:2322–2326 (63/12/2322 [pii])PubMedGoogle Scholar
  4. 4.
    Bassuk SS, Glass TA, Berkman LF (1999) Social disengagement and incident cognitive decline in community-dwelling elderly persons. Ann Intern Med 131:165–173 (199908030-00002 [pii])PubMedGoogle Scholar
  5. 5.
    Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS (2006) The effect of social networks on the relation between Alzheimer’s disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurol 5:406–412 (S1474-4422(06)70417-3 [pii])PubMedGoogle Scholar
  6. 6.
    Bernberg E, Andersson IJ, Gan LM, Naylor AS, Johansson ME, Bergstrom G (2008) Effects of social isolation and environmental enrichment on atherosclerosis in ApoE−/− mice. Stress 11:381–389. doi:10.1080/10253890701824051 PubMedGoogle Scholar
  7. 7.
    Boden-Albala B, Litwak E, Elkind MS, Rundek T, Sacco RL (2005) Social isolation and outcomes post stroke. Neurology 64:1888–1892 (64/11/1888 [pii])PubMedGoogle Scholar
  8. 8.
    Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462. doi:10.1038/35013070 PubMedGoogle Scholar
  9. 9.
    Brezinka V, Kittel F (1996) Psychosocial factors of coronary heart disease in women: a review. Soc Sci Med 42:1351–1365 (0277953695002847 [pii])PubMedGoogle Scholar
  10. 10.
    Brummett BH, Barefoot JC, Siegler IC, Clapp-Channing NE, Lytle BL, Bosworth HB, Williams RB Jr, Mark DB (2001) Characteristics of socially isolated patients with coronary artery disease who are at elevated risk for mortality. Psychosom Med 63:267–272PubMedGoogle Scholar
  11. 11.
    Bucholz EM, Rathore SS, Gosch K, Schoenfeld A, Jones PG, Buchanan DM, Spertus JA, Krumholz HM (2011) Effect of living alone on patient outcomes after hospitalization for acute myocardial infarction. Am J Cardiol 108:943–948. doi:10.1016/j.amjcard.2011.05.023 PubMedCentralPubMedGoogle Scholar
  12. 12.
    Butler TR, Ariwodola OJ, Weiner JL (2014) The impact of social isolation on HPA axis function, anxiety-like behaviors, and ethanol drinking. Front Integr Neurosci 7:102. doi:10.3389/fnint.2013.00102 PubMedCentralPubMedGoogle Scholar
  13. 13.
    Cacioppo JT, Hawkley LC (2003) Social isolation and health, with an emphasis on underlying mechanisms. Perspect Biol Med 46:S39–S52PubMedGoogle Scholar
  14. 14.
    Cassel J (1976) The contribution of the social environment to host resistance: the Fourth Wade Hampton Frost Lecture. Am J Epidemiol 104:107–123PubMedGoogle Scholar
  15. 15.
    Cene CW, Loehr L, Lin FC, Hammond WP, Foraker RE, Rose K, Mosley T, Corbie-Smith G (2012) Social isolation, vital exhaustion, and incident heart failure: findings from the Atherosclerosis Risk in Communities Study. Eur J Heart Fail 14:748–753. doi:10.1093/eurjhf/hfs064 PubMedCentralPubMedGoogle Scholar
  16. 16.
    Cobb S (1976) Presidential Address-1976. Social support as a moderator of life stress. Psychosom Med 38:300–314PubMedGoogle Scholar
  17. 17.
    Colaianna M, Schiavone S, Zotti M, Tucci P, Morgese MG, Backdahl L, Holmdahl R, Krause KH, Cuomo V, Trabace L (2013) Neuroendocrine profile in a rat model of psychosocial stress: relation to oxidative stress. Antioxid Redox Signal 18:1385–1399. doi:10.1089/ars.2012.4569 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Cole SW (2008) Social regulation of leukocyte homeostasis: the role of glucocorticoid sensitivity. Brain Behav Immun 22:1049–1055. doi:10.1016/j.bbi.2008.02.006 PubMedCentralPubMedGoogle Scholar
  19. 19.
    Cole SW, Hawkley LC, Arevalo JM, Sung CY, Rose RM, Cacioppo JT (2007) Social regulation of gene expression in human leukocytes. Genome Biol 8:R189 (gb-2007-8-9-r189 [pii])PubMedCentralPubMedGoogle Scholar
  20. 20.
    Craft TK, DeVries AC (2006) Role of IL-1 in poststroke depressive-like behavior in mice. Biol Psychiatry 60:812–818 (S0006-3223(06)00376-3 [pii])PubMedGoogle Scholar
  21. 21.
    Craft TK, Glasper ER, McCullough L, Zhang N, Sugo N, Otsuka T, Hurn PD, DeVries AC (2005) Social interaction improves experimental stroke outcome. Stroke 36:2006–2011 (01.STR.0000177538.17687.54 [pii])PubMedGoogle Scholar
  22. 22.
    Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, Morris JC (2006) Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia. Am J Psychiatry 163:2164–2169 (163/12/2164 [pii])PubMedCentralPubMedGoogle Scholar
  23. 23.
    Dale DC, Fauci AS, Guerry DIV, Wolff SM (1975) Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. J Clin Invest 56:808–813. doi:10.1172/JCI108159 PubMedCentralPubMedGoogle Scholar
  24. 24.
    de Jong-Gierveld J, Kamphuis F, Dykstra P (1987) Old and lonely? Compr Gerontol B 1:13–17PubMedGoogle Scholar
  25. 25.
    DeVries AC, Craft TK, Glasper ER, Neigh GN, Alexander JK (2007) 2006 Curt P. Richter award winner: Social influences on stress responses and health. Psychoneuroendocrinology 32:587–603 (S0306-4530(07)00084-4 [pii])PubMedGoogle Scholar
  26. 26.
    Dickerson SS, Kemeny ME (2004) Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 130:355–391. doi:10.1037/0033-2909.130.3.355 PubMedGoogle Scholar
  27. 27.
    Dobarro M, Gerenu G, Ramirez MJ (2013) Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer’s transgenic mice. Int J Neuropsychopharmacol 16:2245–2257. doi:10.1017/S1461145713000631 PubMedGoogle Scholar
  28. 28.
    Dong H, Goico B, Martin M, Csernansky CA, Bertchume A, Csernansky JG (2004) Modulation of hippocampal cell proliferation, memory, and amyloid plaque deposition in APPsw (Tg2576) mutant mice by isolation stress. Neuroscience 127:601–609. doi:10.1016/j.neuroscience.2004.05.040 PubMedGoogle Scholar
  29. 29.
    Dong H, Yuede CM, Yoo HS, Martin MV, Deal C, Mace AG, Csernansky JG (2008) Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience 155:154–163. doi:10.1016/j.neuroscience.2008.05.017 PubMedCentralPubMedGoogle Scholar
  30. 30.
    Drageset J, Eide GE, Kirkevold M, Ranhoff AH (2013) Emotional loneliness is associated with mortality among mentally intact nursing home residents with and without cancer: a five-year follow-up study. J Clin Nurs 22:106–114. doi:10.1111/j.1365-2702.2012.04209.x PubMedGoogle Scholar
  31. 31.
    Eisenberger NI, Taylor SE, Gable SL, Hilmert CJ, Lieberman MD (2007) Neural pathways link social support to attenuated neuroendocrine stress responses. Neuroimage 35:1601–1612 (S1053-8119(07)00085-7 [pii])PubMedCentralPubMedGoogle Scholar
  32. 32.
    Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000) The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638PubMedGoogle Scholar
  33. 33.
    Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JC, Breteler MM (2004) Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol 61:668–672. doi:10.1001/archneur.61.5.668 PubMedGoogle Scholar
  34. 34.
    Ertel KA, Glymour MM, Berkman LF (2008) Effects of social integration on preserving memory function in a nationally representative US elderly population. Am J Public Health 98:1215–1220. doi:10.2105/AJPH.2007.113654 PubMedCentralPubMedGoogle Scholar
  35. 35.
    Feibel JH, Hardy PM, Campbell RG, Goldstein MN, Joynt RJ (1977) Prognostic value of the stress response following stroke. JAMA 238:1374–1376PubMedGoogle Scholar
  36. 36.
    Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, Alzheimer’s Disease International (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–2117 (S0140-6736(05)67889-0 [pii])PubMedCentralPubMedGoogle Scholar
  37. 37.
    Gafarov VV, Panov DO, Gromova EA, Gagulin IV, Gafarova AV (2013) The influence of social support on risk of acute cardiovascular diseases in female population aged 25–64 in Russia. Int J Circumpolar Health 72. doi:10.3402/ijch.v72i0.21210 (eCollection 2013)
  38. 38.
    Glass TA, Maddox GL (1992) The quality and quantity of social support: stroke recovery as psycho-social transition. Soc Sci Med 34:1249–1261PubMedGoogle Scholar
  39. 39.
    Grant N, Hamer M, Steptoe A (2009) Social isolation and stress-related cardiovascular, lipid, and cortisol responses. Ann Behav Med 37:29–37. doi:10.1007/s12160-009-9081-z PubMedGoogle Scholar
  40. 40.
    Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 26:9047–9056 (26/35/9047 [pii])PubMedGoogle Scholar
  41. 41.
    Grippo AJ, Lamb DG, Carter CS, Porges SW (2007) Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors. Biol Psychiatry 62:1162–1170 (S0006-3223(07)00366-6 [pii])PubMedCentralPubMedGoogle Scholar
  42. 42.
    Grippo AJ, Trahanas DM, Zimmerman RR 2nd, Porges SW, Carter CS (2009) Oxytocin protects against negative behavioral and autonomic consequences of long-term social isolation. Psychoneuroendocrinology 34:1542–1553. doi:10.1016/j.psyneuen.2009.05.017 PubMedCentralPubMedGoogle Scholar
  43. 43.
    Hatmi ZN, Nasiri LF, Sadegianmehr Z, Mirkia S, Darbooy S (2011) Association of myocardial infarction with stressful life events and psychiatric symptoms: a population-based survey. East Mediterr Health J 17:398–403PubMedGoogle Scholar
  44. 44.
    Hawkley LC, Cacioppo JT (2010) Loneliness matters: a theoretical and empirical review of consequences and mechanisms. Ann Behav Med 40:218–227. doi:10.1007/s12160-010-9210-8 PubMedGoogle Scholar
  45. 45.
    Heffner KL, Waring ME, Roberts MB, Eaton CB, Gramling R (2011) Social isolation, C-reactive protein, and coronary heart disease mortality among community-dwelling adults. Soc Sci Med 72:1482–1488. doi:10.1016/j.socscimed.2011.03.016 PubMedCentralPubMedGoogle Scholar
  46. 46.
    Helmer C, Damon D, Letenneur L, Fabrigoule C, Barberger-Gateau P, Lafont S, Fuhrer R, Antonucci T, Commenges D, Orgogozo JM, Dartigues JF (1999) Marital status and risk of Alzheimer’s disease: a French population-based cohort study. Neurology 53:1953–1958PubMedGoogle Scholar
  47. 47.
    Helmy AA, Naseer MM, Shafie SE, Nada MA (2012) Role of interleukin 6 and alpha-globulins in differentiating Alzheimer and vascular dementias. Neurodegener Dis 9:81–86. doi:10.1159/000329568 PubMedGoogle Scholar
  48. 48.
    Henderson AS, Scott R, Kay DW (1986) The elderly who live alone: their mental health and social relationships. Aust NZ J Psychiatry 20:202–209Google Scholar
  49. 49.
    Henderson KM, Clark CJ, Lewis TT, Aggarwal NT, Beck T, Guo H, Lunos S, Brearley A, Mendes de Leon CF, Evans DA, Everson-Rose SA (2013) Psychosocial distress and stroke risk in older adults. Stroke 44:367–372. doi:10.1161/STROKEAHA.112.679159 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, Culliford D, Perry VH (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73:768–774. doi:10.1212/WNL.0b013e3181b6bb95 PubMedCentralPubMedGoogle Scholar
  51. 51.
    Holt-Lunstad J, Smith TB, Layton JB (2010) Social relationships and mortality risk: a meta-analytic review. PLoS Med 7:e1000316. doi:10.1371/journal.pmed.1000316 PubMedCentralPubMedGoogle Scholar
  52. 52.
    House JS (2001) Social isolation kills, but how and why? Psychosom Med 63:273–274PubMedGoogle Scholar
  53. 53.
    House JS, Landis KR, Umberson D (1988) Social relationships and health. Science 241:540–545PubMedGoogle Scholar
  54. 54.
    House JS, Robbins C, Metzner HL (1982) The association of social relationships and activities with mortality: prospective evidence from the Tecumseh Community Health Study. Am J Epidemiol 116:123–140PubMedGoogle Scholar
  55. 55.
    Hsiao YH, Kuo JR, Chen SH, Gean PW (2012) Amelioration of social isolation-triggered onset of early Alzheimer’s disease-related cognitive deficit by N-acetylcysteine in a transgenic mouse model. Neurobiol Dis 45:1111–1120. doi:10.1016/j.nbd.2011.12.031 PubMedGoogle Scholar
  56. 56.
    Hsiao YH, Chen PS, Chen SH, Gean PW (2011) The involvement of Cdk5 activator p35 in social isolation-triggered onset of early Alzheimer’s disease-related cognitive deficit in the transgenic mice. Neuropsychopharmacology 36:1848–1858. doi:10.1038/npp.2011.69 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Huang CW, Lui CC, Chang WN, Lu CH, Wang YL, Chang CC (2009) Elevated basal cortisol level predicts lower hippocampal volume and cognitive decline in Alzheimer’s disease. J Clin Neurosci 16:1283–1286. doi:10.1016/j.jocn.2008.12.026 PubMedGoogle Scholar
  58. 58.
    Huang HJ, Liang KC, Ke HC, Chang YY, Hsieh-Li HM (2011) Long-term social isolation exacerbates the impairment of spatial working memory in APP/PS1 transgenic mice. Brain Res 1371:150–160. doi:10.1016/j.brainres.2010.11.043 PubMedGoogle Scholar
  59. 59.
    Ikeda A, Kawachi I, Iso H, Iwasaki M, Inoue M, Tsugane S (2013) Social support and cancer incidence and mortality: the JPHC study cohort II. Cancer Causes Control 24:847–860. doi:10.1007/s10552-013-0147-7 PubMedGoogle Scholar
  60. 60.
    Ikram MA, Vrooman HA, Vernooij MW, den Heijer T, Hofman A, Niessen WJ, van der Lugt A, Koudstaal PJ, Breteler MM (2010) Brain tissue volumes in relation to cognitive function and risk of dementia. Neurobiol Aging 31:378–386. doi:10.1016/j.neurobiolaging.2008.04.008 PubMedGoogle Scholar
  61. 61.
    James BD, Glass TA, Caffo B, Bobb JF, Davatzikos C, Yousem D, Schwartz BS (2012) Association of social engagement with brain volumes assessed by structural MRI. J Aging Res 2012:512714. doi:10.1155/2012/512714 PubMedCentralPubMedGoogle Scholar
  62. 62.
    Jeong HG, Lee JJ, Lee SB, Park JH, Huh Y, Han JW, Kim TH, Chin HJ, Kim KW (2013) Role of severity and gender in the association between late-life depression and all-cause mortality. Int Psychogeriatr 25:677–684. doi:10.1017/S1041610212002190 PubMedGoogle Scholar
  63. 63.
    Kaplan GA, Salonen JT, Cohen RD, Brand RJ, Syme SL, Puska P (1988) Social connections and mortality from all causes and from cardiovascular disease: prospective evidence from eastern Finland. Am J Epidemiol 128:370–380PubMedGoogle Scholar
  64. 64.
    Kaplan JR, Manuck SB, Clarkson TB, Lusso FM, Taub DM (1982) Social status, environment, and atherosclerosis in cynomolgus monkeys. Arteriosclerosis 2:359–368PubMedGoogle Scholar
  65. 65.
    Karelina K, Norman GJ, Zhang N, DeVries AC (2009) Social contact influences histological and behavioral outcomes following cerebral ischemia. Exp Neurol 220:276–282. doi:10.1016/j.expneurol.2009.08.022 PubMedGoogle Scholar
  66. 66.
    Karelina K, Norman GJ, Zhang N, Morris JS, Peng H, DeVries AC (2009) Social isolation alters neuroinflammatory response to stroke. Proc Natl Acad Sci USA 106:5895–5900. doi:10.1073/pnas.0810737106 PubMedCentralPubMedGoogle Scholar
  67. 67.
    Karelina K, Stuller KA, Jarrett B, Zhang N, Wells J, Norman GJ, DeVries AC (2011) Oxytocin mediates social neuroprotection after cerebral ischemia. Stroke 42:3606–3611. doi:10.1161/STROKEAHA.111.628008 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Katan M, Elkind MS (2011) Inflammatory and neuroendocrine biomarkers of prognosis after ischemic stroke. Expert Rev Neurother 11:225–239. doi:10.1586/ern.10.200 PubMedGoogle Scholar
  69. 69.
    Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A (1988) Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 23:138–144. doi:10.1002/ana.410230206 PubMedGoogle Scholar
  70. 70.
    Kawachi I, Colditz GA, Ascherio A, Rimm EB, Giovannucci E, Stampfer MJ, Willett WC (1996) A prospective study of social networks in relation to total mortality and cardiovascular disease in men in the USA. J Epidemiol Community Health 50:245–251PubMedCentralPubMedGoogle Scholar
  71. 71.
    Kitamura T, Sakata Y, Nakatani D, Suna S, Usami M, Matsumoto S, Hara M, Hamasaki T, Nanto S, Sato H, Hori M, Iso H, Komuro I (2013) Living alone and risk of cardiovascular events following discharge after acute myocardial infarction in Japan. J Cardiol 62:257–262. doi:10.1016/j.jjcc.2013.04.009 PubMedGoogle Scholar
  72. 72.
    Knoops AJ, Gerritsen L, van der Graaf Y, Mali WP, Geerlings MI (2010) Basal hypothalamic pituitary adrenal axis activity and hippocampal volumes: the SMART-Medea study. Biol Psychiatry 67:1191–1198. doi:10.1016/j.biopsych.2010.01.025 PubMedGoogle Scholar
  73. 73.
    Kunugi H, Hori H, Adachi N, Numakawa T (2010) Interface between hypothalamic–pituitary–adrenal axis and brain-derived neurotrophic factor in depression. Psychiatry Clin Neurosci 64:447–459. doi:10.1111/j.1440-1819.2010.02135.x PubMedGoogle Scholar
  74. 74.
    Lacey RE, Kumari M, Bartley M (2014) Social isolation in childhood and adult inflammation: evidence from the National Child Development Study. Psychoneuroendocrinology 50C:85–94 (S0306-4530(14)00312-6 [pii])Google Scholar
  75. 75.
    Lambertsen KL, Biber K, Finsen B (2012) Inflammatory cytokines in experimental and human stroke. J Cereb Blood Flow Metab 32:1677–1698. doi:10.1038/jcbfm.2012.88 PubMedCentralPubMedGoogle Scholar
  76. 76.
    Lara VP, Caramelli P, Teixeira AL, Barbosa MT, Carmona KC, Carvalho MG, Fernandes AP, Gomes KB (2013) High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia. Clin Chim Acta 423:18–22. doi:10.1016/j.cca.2013.04.013 PubMedGoogle Scholar
  77. 77.
    Lee M, Rotheram-Borus MJ (2001) Challenges associated with increased survival among parents living with HIV. Am J Public Health 91:1303–1309PubMedCentralPubMedGoogle Scholar
  78. 78.
    Li R, Singh M (2014) Sex differences in cognitive impairment and Alzheimer’s disease. Front Neuroendocrinol 35:385–403. doi:10.1016/j.yfrne.2014.01.002 PubMedGoogle Scholar
  79. 79.
    Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann NY Acad Sci 1122:130–143 (1122/1/130 [pii])PubMedGoogle Scholar
  80. 80.
    Liu H, Wang Z (2005) Effects of social isolation stress on immune response and survival time of mouse with liver cancer. World J Gastroenterol 11:5902–5904PubMedGoogle Scholar
  81. 81.
    Loucks EB, Berkman LF, Gruenewald TL, Seeman TE (2006) Relation of social integration to inflammatory marker concentrations in men and women 70–79 years. Am J Cardiol 97:1010–1016 (S0002-9149(05)02221-6 [pii])PubMedGoogle Scholar
  82. 82.
    Loucks EB, Sullivan LM, D’Agostino RBS, Larson MG, Berkman LF, Benjamin EJ (2006) Social networks and inflammatory markers in the Framingham Heart Study. J Biosoc Sci 38:835–842 (S0021932005001203 [pii])PubMedGoogle Scholar
  83. 83.
    Marsland AL, Petersen KL, Sathanoori R, Muldoon MF, Neumann SA, Ryan C, Flory JD, Manuck SB (2006) Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med 68:895–903 (68/6/895 [pii])PubMedGoogle Scholar
  84. 84.
    Miller GE, Cohen S, Ritchey AK (2002) Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 21:531–541PubMedGoogle Scholar
  85. 85.
    Mookadam F, Arthur HM (2004) Social support and its relationship to morbidity and mortality after acute myocardial infarction: systematic overview. Arch Intern Med 164:1514–1518. doi:10.1001/archinte.164.14.1514 PubMedGoogle Scholar
  86. 86.
    Muir KW, Tyrrell P, Sattar N, Warburton E (2007) Inflammation and ischaemic stroke. Curr Opin Neurol 20:334–342. doi:10.1097/WCO.0b013e32813ba151 PubMedGoogle Scholar
  87. 87.
    Munck A, Guyre PM (1986) Glucocorticoid physiology, pharmacology and stress. Adv Exp Med Biol 196:81–96PubMedGoogle Scholar
  88. 88.
    Nagayoshi M, Everson-Rose SA, Iso H, Mosley TH Jr, Rose KM, Lutsey PL (2014) Social network, social support, and risk of incident stroke: atherosclerosis risk in communities study. Stroke 45(10):2868–2873. doi:10.1161/STROKEAHA.114.005815 PubMedGoogle Scholar
  89. 89.
    Nakagawa-Toyama Y, Zhang S, Krieger M (2012) Dietary manipulation and social isolation alter disease progression in a murine model of coronary heart disease. PLoS One 7:e47965. doi:10.1371/journal.pone.0047965 PubMedCentralPubMedGoogle Scholar
  90. 90.
    Nation DA, Szeto A, Mendez AJ, Brooks LG, Zaias J, Herderick EE, Gonzales J, Noller CM, Schneiderman N, McCabe PM (2010) Oxytocin attenuates atherosclerosis and adipose tissue inflammation in socially isolated ApoE−/− mice. Psychosom Med 72:376–382. doi:10.1097/PSY.0b013e3181d74c48 PubMedGoogle Scholar
  91. 91.
    Ni Y, Zhao X, Bao G, Zou L, Teng L, Wang Z, Song M, Xiong J, Bai Y, Pei G (2006) Activation of beta2-adrenergic receptor stimulates gamma-secretase activity and accelerates amyloid plaque formation. Nat Med 12:1390–1396 (nm1485 [pii])PubMedGoogle Scholar
  92. 92.
    Norman GJ, Zhang N, Morris JS, Karelina K, Berntson GG, DeVries AC (2010) Social interaction modulates autonomic, inflammatory, and depressive-like responses to cardiac arrest and cardiopulmonary resuscitation. Proc Natl Acad Sci USA 107:16342–16347. doi:10.1073/pnas.1007583107 PubMedCentralPubMedGoogle Scholar
  93. 93.
    O’Keefe LM, Doran SJ, Mwilambwe-Tshilobo L, Conti LH, Venna VR, McCullough LD (2014) Social isolation after stroke leads to depressive-like behavior and decreased BDNF levels in mice. Behav Brain Res 260:162–170. doi:10.1016/j.bbr.2013.10.047 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Orrell M, Butler R, Bebbington P (2000) Social factors and the outcome of dementia. Int J Geriatr Psychiatry 15:515–520. doi:10.1002/1099-1166(200006)15:6<515:AID-GPS147>3.0.CO;2-U PubMedGoogle Scholar
  95. 95.
    Paredes J, Szeto A, Levine JE, Zaias J, Gonzales JA, Mendez AJ, Llabre MM, Schneiderman N, McCabe PM (2006) Social experience influences hypothalamic oxytocin in the WHHL rabbit. Psychoneuroendocrinology 31:1062–1075 (S0306-4530(06)00130-2 [pii])PubMedGoogle Scholar
  96. 96.
    Patterson TL, Shaw WS, Semple SJ, Cherner M, McCutchan JA, Atkinson JH, Grant I, Nannis E, HIV Neurobehavioral Research Center (HNRC) Group (1996) Relationship of psychosocial factors to HIV disease progression. Ann Behav Med 18:30–39. doi:10.1007/BF02903937 PubMedGoogle Scholar
  97. 97.
    Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32. doi:10.1038/35049004 PubMedGoogle Scholar
  98. 98.
    Popp J, Schaper K, Kolsch H, Cvetanovska G, Rommel F, Klingmuller D, Dodel R, Wullner U, Jessen F (2009) CSF cortisol in Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 30:498–500 (S0197-4580(07)00261-8 [pii])PubMedGoogle Scholar
  99. 99.
    Powell ND, Sloan EK, Bailey MT, Arevalo JM, Miller GE, Chen E, Kobor MS, Reader BF, Sheridan JF, Cole SW (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via beta-adrenergic induction of myelopoiesis. Proc Natl Acad Sci USA 110:16574–16579. doi:10.1073/pnas.1310655110 PubMedCentralPubMedGoogle Scholar
  100. 100.
    Pratico D (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 29:609–615. doi:10.1016/ PubMedGoogle Scholar
  101. 101.
    Quan N, Avitsur R, Stark JL, He L, Lai W, Dhabhar F, Sheridan JF (2003) Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice. J Neuroimmunol 137:51–58 (S0165572803000420 [pii])PubMedGoogle Scholar
  102. 102.
    Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L (2008) Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 7:915–926. doi:10.1016/S1474-4422(08)70193-5 PubMedCentralPubMedGoogle Scholar
  103. 103.
    Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353:1711–1723 (353/16/1711 [pii])PubMedGoogle Scholar
  104. 104.
    Rozanski A, Blumenthal JA, Kaplan J (1999) Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 99:2192–2217PubMedGoogle Scholar
  105. 105.
    Rutledge T, Reis SE, Olson M, Owens J, Kelsey SF, Pepine CJ, Mankad S, Rogers WJ, Bairey Merz CN, Sopko G, Cornell CE, Sharaf B, Matthews KA, National Heart, Lung, and Blood Institute (2004) Social networks are associated with lower mortality rates among women with suspected coronary disease: the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation study. Psychosom Med 66:882–888 (66/6/882 [pii])PubMedGoogle Scholar
  106. 106.
    Rutledge T, Linke SE, Olson MB, Francis J, Johnson BD, Bittner V, York K, McClure C, Kelsey SF, Reis SE, Cornell CE, Vaccarino V, Sheps DS, Shaw LJ, Krantz DS, Parashar S, Merz CN (2008) Social networks and incident stroke among women with suspected myocardial ischemia. Psychosom Med 70:282–287. doi:10.1097/PSY.0b013e3181656e09 PubMedGoogle Scholar
  107. 107.
    Saczynski JS, Pfeifer LA, Masaki K, Korf ES, Laurin D, White L, Launer LJ (2006) The effect of social engagement on incident dementia: the Honolulu-Asia Aging Study. Am J Epidemiol 163:433–440 (kwj061 [pii])PubMedGoogle Scholar
  108. 108.
    Saresella M, Marventano I, Calabrese E, Piancone F, Rainone V, Gatti A, Alberoni M, Nemni R, Clerici M (2014) A complex proinflammatory role for peripheral monocytes in Alzheimer’s disease. J Alzheimers Dis 38:403–413. doi:10.3233/JAD-131160 PubMedGoogle Scholar
  109. 109.
    Schmaltz HN, Southern D, Ghali WA, Jelinski SE, Parsons GA, King KM, Maxwell CJ (2007) Living alone, patient sex and mortality after acute myocardial infarction. J Gen Intern Med 22:572–578. doi:10.1007/s11606-007-0106-7 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Schoenfeld TJ, Gould E (2012) Stress, stress hormones, and adult neurogenesis. Exp Neurol 233:12–21. doi:10.1016/j.expneurol.2011.01.008 PubMedCentralPubMedGoogle Scholar
  111. 111.
    Serra M, Pisu MG, Floris I, Biggio G (2005) Social isolation-induced changes in the hypothalamic–pituitary–adrenal axis in the rat. Stress 8:259–264 (P0R2346T77643492 [pii])PubMedGoogle Scholar
  112. 112.
    Simpson EE, Hodkinson CF, Maylor EA, McCormack JM, Rae G, Strain S, Alexander HD, Wallace JM (2013) Intracellular cytokine production and cognition in healthy older adults. Psychoneuroendocrinology 38:2196–2208. doi:10.1016/j.psyneuen.2013.04.007 PubMedGoogle Scholar
  113. 113.
    Smith MA (1996) Hippocampal vulnerability to stress and aging: possible role of neurotrophic factors. Behav Brain Res 78:25–36 (0166432895002200 [pii])PubMedGoogle Scholar
  114. 114.
    Spencer SJ, Mouihate A, Pittman QJ (2007) Peripheral inflammation exacerbates damage after global ischemia independently of temperature and acute brain inflammation. Stroke 38:1570–1577 (STROKEAHA.106.476507 [pii])PubMedGoogle Scholar
  115. 115.
    Steffener J, Stern Y (2012) Exploring the neural basis of cognitive reserve in aging. Biochim Biophys Acta 1822:467–473. doi:10.1016/j.bbadis.2011.09.012 PubMedCentralPubMedGoogle Scholar
  116. 116.
    Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol 11:1006–1012. doi:10.1016/S1474-4422(12)70191-6 PubMedCentralPubMedGoogle Scholar
  117. 117.
    Stuller KA, Jarrett B, DeVries AC (2012) Stress and social isolation increase vulnerability to stroke. Exp Neurol 233:33–39. doi:10.1016/j.expneurol.2011.01.016 PubMedGoogle Scholar
  118. 118.
    Sudheimer KD, O’Hara R, Spiegel D, Powers B, Kraemer HC, Neri E, Weiner M, Hardan A, Hallmayer J, Dhabhar FS (2014) Cortisol, cytokines, and hippocampal volume interactions in the elderly. Front Aging Neurosci 6:153. doi:10.3389/fnagi.2014.00153 PubMedCentralPubMedGoogle Scholar
  119. 119.
    Sugo N, Hurn PD, Morahan MB, Hattori K, Traystman RJ, DeVries AC (2002) Social stress exacerbates focal cerebral ischemia in mice. Stroke 33:1660–1664PubMedGoogle Scholar
  120. 120.
    Suri D, Vaidya VA (2013) Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity. Neuroscience 239:196–213. doi:10.1016/j.neuroscience.2012.08.065 PubMedGoogle Scholar
  121. 121.
    Szeto A, Nation DA, Mendez AJ, Dominguez-Bendala J, Brooks LG, Schneiderman N, McCabe PM (2008) Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. Am J Physiol Endocrinol Metab 295:E1495–E1501. doi:10.1152/ajpendo.90718.2008 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Takatsu-Coleman AL, Patti CL, Zanin KA, Zager A, Carvalho RC, Borcoi AR, Ceccon LM, Berro LF, Tufik S, Andersen ML, Frussa-Filho R (2013) Short-term social isolation induces depressive-like behaviour and reinstates the retrieval of an aversive task: mood-congruent memory in male mice? J Psychiatry Neurosci 38:259–268. doi:10.1503/jpn.120050 PubMedCentralPubMedGoogle Scholar
  123. 123.
    Toledo JB, Toledo E, Weiner MW, Jack CR Jr, Jagust W, Lee VM, Shaw LM, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative (2012) Cardiovascular risk factors, cortisol, and amyloid-beta deposition in Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement 8:483–489. doi:10.1016/j.jalz.2011.08.008 PubMedCentralPubMedGoogle Scholar
  124. 124.
    Tu WJ, Dong X, Zhao SJ, Yang DG, Chen H (2013) Prognostic value of plasma neuroendocrine biomarkers in patients with acute ischaemic stroke. J Neuroendocrinol 25:771–778. doi:10.1111/jne.12052 PubMedGoogle Scholar
  125. 125.
    Uchoa ET, Aguilera G, Herman JP, Fiedler JL, Deak T, de Sousa MB (2014) Novel aspects of glucocorticoid actions. J Neuroendocrinol 26:557–572. doi:10.1111/jne.12157 PubMedCentralPubMedGoogle Scholar
  126. 126.
    Udell JA, Steg PG, Scirica BM, Smith SC Jr, Ohman EM, Eagle KA, Goto S, Cho JI, Bhatt DL, REduction of Atherothrombosis for Continued Health (REACH) Registry Investigators (2012) Living alone and cardiovascular risk in outpatients at risk of or with atherothrombosis. Arch Intern Med 172:1086–1095 (1188041 [pii])PubMedGoogle Scholar
  127. 127.
    Venna VR, Xu Y, Doran SJ, Patrizz A, McCullough LD (2014) Social interaction plays a critical role in neurogenesis and recovery after stroke. Transl Psychiatry 4:e351. doi:10.1038/tp.2013.128 PubMedCentralPubMedGoogle Scholar
  128. 128.
    Venna VR, Verma R, O’Keefe LM, Xu Y, Crapser J, Friedler B, McCullough LD (2014) Inhibition of mitochondrial p53 abolishes the detrimental effects of social isolation on ischemic brain injury. Stroke 45(10):3101–3104. doi:10.1161/STROKEAHA.114.006553 PubMedGoogle Scholar
  129. 129.
    Venna VR, Weston G, Benashski SE, Tarabishy S, Liu F, Li J, Conti LH, McCullough LD (2012) NF-kappaB contributes to the detrimental effects of social isolation after experimental stroke. Acta Neuropathol 124:425–438. doi:10.1007/s00401-012-0990-8 PubMedCentralPubMedGoogle Scholar
  130. 130.
    Verma R, Friedler BD, Harris NM, McCullough LD (2014) Pair housing reverses post-stroke depressive behavior in mice. Behav Brain Res 269:155–163. doi:10.1016/j.bbr.2014.04.044 PubMedGoogle Scholar
  131. 131.
    Vespa J, Lewis JM, Kreider RM (2013) America’s families and living arrangements: 2012. Current Population Reports P20–570. pp 1–34. U.S. Census Bureau, Washington, DCGoogle Scholar
  132. 132.
    Victor CR, Bowling A, Bond J, Scambler S (2003) Loneliness, social isolation and living alone in later life. ESRC Growing Older Programme, SheffieldGoogle Scholar
  133. 133.
    Wang HX, Karp A, Winblad B, Fratiglioni L (2002) Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. Am J Epidemiol 155:1081–1087PubMedGoogle Scholar
  134. 134.
    Wang X, Wu H, Miller AH (2004) Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry 9:65–75. doi:10.1038/ PubMedGoogle Scholar
  135. 135.
    Weil ZM, Norman GJ, Barker JM, Su AJ, Nelson RJ, Devries AC (2008) Social isolation potentiates cell death and inflammatory responses after global ischemia. Mol Psychiatry 13:913–915. doi:10.1038/mp.2008.70 PubMedCentralPubMedGoogle Scholar
  136. 136.
    Whiteley W, Jackson C, Lewis S, Lowe G, Rumley A, Sandercock P, Wardlaw J, Dennis M, Sudlow C (2011) Association of circulating inflammatory markers with recurrent vascular events after stroke: a prospective cohort study. Stroke 42:10–16. doi:10.1161/STROKEAHA.110.588954 PubMedCentralPubMedGoogle Scholar
  137. 137.
    Wingard DL, Cohn BA (1987) Coronary heart disease mortality among women in Alameda County, 1965–1973. In: Eaker ED, Packard B, Wenger NK, Clarkson TB, Tyroler HA (eds) Coronary heart disease in Women. Haymarket Doyma, New York, pp 99–105Google Scholar
  138. 138.
    Wisely EV, Xiang YK, Oddo S (2014) Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet 23:4024–4034. doi:10.1093/hmg/ddu116 PubMedGoogle Scholar
  139. 139.
    Wolf OT, Convit A, de Leon MJ, Caraos C, Qadri SF (2002) Basal hypothalamo–pituitary–adrenal axis activity and corticotropin feedback in young and older men: relationships to magnetic resonance imaging-derived hippocampus and cingulate gyrus volumes. Neuroendocrinology 75:241–249 (54715 [pii])PubMedGoogle Scholar
  140. 140.
    Yang YC, McClintock MK, Kozloski M, Li T (2013) Social isolation and adult mortality: the role of chronic inflammation and sex differences. J Health Soc Behav 54:183–203. doi:10.1177/0022146513485244 PubMedCentralPubMedGoogle Scholar
  141. 141.
    Yu NN, Wang XX, Yu JT, Wang ND, Lu RC, Miao D, Tian Y, Tan L (2010) Blocking beta2-adrenergic receptor attenuates acute stress-induced amyloid beta peptides production. Brain Res 1317:305–310. doi:10.1016/j.brainres.2009.12.087 PubMedGoogle Scholar
  142. 142.
    Zhou J, Yu JT, Wang HF, Meng XF, Tan CC, Wang J, Wang C, Tan L (2015) Association between stroke and Alzheimer’s disease: systematic review and meta-analysis. J Alzheimers Dis 43(2):479–489. doi:10.3233/JAD-140666 PubMedGoogle Scholar
  143. 143.
    Zlatkovic J, Filipovic D (2013) Chronic social isolation induces NF-kappaB activation and upregulation of iNOS protein expression in rat prefrontal cortex. Neurochem Int 63:172–179. doi:10.1016/j.neuint.2013.06.002 PubMedGoogle Scholar
  144. 144.
    Zuidersma M, Conradi HJ, van Melle JP, Ormel J, de Jonge P (2013) Self-reported depressive symptoms, diagnosed clinical depression and cardiac morbidity and mortality after myocardial infarction. Int J Cardiol 167:2775–2780. doi:10.1016/j.ijcard.2012.07.002 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Brett Friedler
    • 1
  • Joshua Crapser
    • 1
  • Louise McCullough
    • 1
    • 2
  1. 1.Department of NeuroscienceUniversity of Connecticut Health CenterFarmingtonUSA
  2. 2.The Stroke Center at Hartford HospitalHartfordUSA

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