Clinical trial NCT04586049: Cardiovascular and Neurovascular Regulation in GWI
Official title: Autonomic Dysfunction, Brain Blood Flow and Cognitive Decline in Veterans With Gulf War Illness
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Brain Blood Flow
Neurovascular Control
Keywords: MRI
Brain Blood Flow
Sympathetic Nerve Activity
Cardiorespiratory Fitness
Lead sponsor: University of Wisconsin, Madison
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2020-10-14
Enrollment: 70
Sex: ALL
Minimum age (years): 45
Maximum age (years): 68
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects for this study will include Veterans with Gulf War Illness and Veterans without Gulf War Illness. Both men and women are eligible to participate in this study.

Brief summary: Brain blood flow regulation and autonomic dysfunction will be measured in Veterans with and without Gulf War Illness who served in the Gulf War between 1990 and 1992.

Detailed description: Gulf War Illness (GWI) is a multi-symptom illness with unknown etiology. GWI is a leading cause of disability in Gulf War Veterans. Cognitive complaints are a common symptom of GWI, which suggests the brain is involved in the development of this condition. As Veterans age, these cognitive complaints may worsen and be compounded by the aging process. GWI may be a condition of "accelerated" brain aging. Therefore, there may be long-term consequences of GWI, and the presence of GWI may increase a person's risk for developing Alzheimer's Disease (AD) or other dementias. In comparison to other brain-related diseases such as stroke, relatively little is known about GWI and how this condition impacts the normal age-related changes in the brain.

The research aims are:

1. To determine if Veterans with Gulf War Illness demonstrate abnormal brain blood flow regulation and autonomic dysfunction when compared with Veterans without Gulf War Illness.
2. To determine if brain blood flow and autonomic nervous system variables in Veterans are associated with other markers of brain aging that are relevant to cognitive decline.

Eligibility criteria: Inclusion Criteria:

* Deployed to the Persian Gulf between 1990-1992
* Body mass \<300 lbs
* Diagnosis of Gulf War Illness based on CMI/CDC and Kansas definitions or No diagnosis of Gulf War Illness

Exclusion Criteria:

* Current or lifetime evidence of: Type II diabetes, neurological disease, cancer treatment, rheumatoid arthritis, lupus, bipolar disorder, psychotic disorders, or mood disorders with psychotic features
* Current illicit substance use or partial remission for less than 1 year
* Taking multiple sedatives or anticonvulsant medications
* Currently pregnant
* Absolute contraindications to exercise testing
* Contraindications to MRI
* Other significant medical conditions at investigator's discretion

Primary outcomes:
measure: Brain blood flow measured using Transcranial Doppler ultrasound
timeFrame: Baseline
measure: Brain blood flow measured using MRI
timeFrame: Baseline
measure: Sympathetic nerve activity
timeFrame: Baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
Study officials:
affiliation: University of Wisconsin, Madison
name: Jill N Barnes, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lecrux C, Hamel E. The neurovascular unit in brain function and disease. Acta Physiol (Oxf). 2011 Sep;203(1):47-59. doi: 10.1111/j.1748-1716.2011.02256.x. Epub 2011 Mar 22.
citation: Catchlove SJ, Parrish TB, Chen Y, Macpherson H, Hughes ME, Pipingas A. Regional Cerebrovascular Reactivity and Cognitive Performance in Healthy Aging. J Exp Neurosci. 2018 Jul 5;12:1179069518785151. doi: 10.1177/1179069518785151. eCollection 2018.
citation: Lange G, Tiersky LA, Scharer JB, Policastro T, Fiedler N, Morgan TE, Natelson BH. Cognitive functioning in Gulf War Illness. J Clin Exp Neuropsychol. 2001 Apr;23(2):240-9. doi: 10.1076/jcen.23.2.240.1208.
citation: Toomey R, Alpern R, Vasterling JJ, Baker DG, Reda DJ, Lyons MJ, Henderson WG, Kang HK, Eisen SA, Murphy FM. Neuropsychological functioning of U.S. Gulf War veterans 10 years after the war. J Int Neuropsychol Soc. 2009 Sep;15(5):717-29. doi: 10.1017/S1355617709990294. Epub 2009 Jul 29.
citation: Bunegin L, Mitzel HC, Miller CS, Gelineau JF, Tolstykh GP. Cognitive performance and cerebrohemodynamics associated with the Persian Gulf Syndrome. Toxicol Ind Health. 2001 May;17(4):128-37. doi: 10.1191/0748233701th100oa.
citation: Hubbard NA, Hutchison JL, Motes MA, Shokri-Kojori E, Bennett IJ, Brigante RM, Haley RW, Rypma B. Central Executive Dysfunction and Deferred Prefrontal Processing in Veterans with Gulf War Illness. Clin Psychol Sci. 2014 May 1;2(3):319-327. doi: 10.1177/2167702613506580.
citation: Christova P, James LM, Engdahl BE, Lewis SM, Carpenter AF, Georgopoulos AP. Subcortical brain atrophy in Gulf War Illness. Exp Brain Res. 2017 Sep;235(9):2777-2786. doi: 10.1007/s00221-017-5010-8. Epub 2017 Jun 20.
citation: Chao LL, Rothlind JC, Cardenas VA, Meyerhoff DJ, Weiner MW. Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans. Neurotoxicology. 2010 Sep;31(5):493-501. doi: 10.1016/j.neuro.2010.05.006. Epub 2010 May 24.
citation: Van Riper SM, Alexander AL, Koltyn KF, Stegner AJ, Ellingson LD, Destiche DJ, Dougherty RJ, Lindheimer JB, Cook DB. Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain. Pain. 2017 Dec;158(12):2364-2375. doi: 10.1097/j.pain.0000000000001038.
citation: Pop V, Sorensen DW, Kamper JE, Ajao DO, Murphy MP, Head E, Hartman RE, Badaut J. Early brain injury alters the blood-brain barrier phenotype in parallel with beta-amyloid and cognitive changes in adulthood. J Cereb Blood Flow Metab. 2013 Feb;33(2):205-14. doi: 10.1038/jcbfm.2012.154. Epub 2012 Nov 14.
citation: Ikonomovic MD, Mi Z, Abrahamson EE. Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev. 2017 Mar;34:51-63. doi: 10.1016/j.arr.2016.11.003. Epub 2016 Nov 6.
citation: Johnson VE, Stewart W, Smith DH. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer's disease? Nat Rev Neurosci. 2010 May;11(5):361-70. doi: 10.1038/nrn2808.
citation: Barnes JN. Exercise, cognitive function, and aging. Adv Physiol Educ. 2015 Jun;39(2):55-62. doi: 10.1152/advan.00101.2014.
citation: Barnes JN, Schmidt JE, Nicholson WT, Joyner MJ. Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia. J Appl Physiol (1985). 2012 Jun;112(11):1884-90. doi: 10.1152/japplphysiol.01270.2011. Epub 2012 Mar 22.
citation: Coverdale NS, Badrov MB, Shoemaker JK. Impact of age on cerebrovascular dilation versus reactivity to hypercapnia. J Cereb Blood Flow Metab. 2017 Jan;37(1):344-355. doi: 10.1177/0271678X15626156. Epub 2016 Jan 12.
citation: Miller KB, Howery AJ, Harvey RE, Eldridge MW, Barnes JN. Cerebrovascular Reactivity and Central Arterial Stiffness in Habitually Exercising Healthy Adults. Front Physiol. 2018 Aug 17;9:1096. doi: 10.3389/fphys.2018.01096. eCollection 2018.
citation: Barnes JN, Harvey RE, Miller KB, Jayachandran M, Malterer KR, Lahr BD, Bailey KR, Joyner MJ, Miller VM. Cerebrovascular Reactivity and Vascular Activation in Postmenopausal Women With Histories of Preeclampsia. Hypertension. 2018 Jan;71(1):110-117. doi: 10.1161/HYPERTENSIONAHA.117.10248. Epub 2017 Nov 20.
citation: Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 2017 Jul;18(7):419-434. doi: 10.1038/nrn.2017.48. Epub 2017 May 18.
citation: Fabiani M, Gordon BA, Maclin EL, Pearson MA, Brumback-Peltz CR, Low KA, McAuley E, Sutton BP, Kramer AF, Gratton G. Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study. Neuroimage. 2014 Jan 15;85 Pt 1(0 1):592-607. doi: 10.1016/j.neuroimage.2013.04.113. Epub 2013 May 9.
citation: Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol (1985). 2006 Jan;100(1):328-35. doi: 10.1152/japplphysiol.00966.2005.
citation: Janulewicz PA, Krengel MH, Maule A, White RF, Cirillo J, Sisson E, Heeren T, Sullivan K. Neuropsychological characteristics of Gulf War illness: A meta-analysis. PLoS One. 2017 May 17;12(5):e0177121. doi: 10.1371/journal.pone.0177121. eCollection 2017.
citation: Haley RW, Spence JS, Carmack PS, Gunst RF, Schucany WR, Petty F, Devous MD Sr, Bonte FJ, Trivedi MH. Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War. Psychiatry Res. 2009 Mar 31;171(3):207-20. doi: 10.1016/j.pscychresns.2008.05.004. Epub 2009 Feb 20.
citation: Li X, Spence JS, Buhner DM, Hart J Jr, Cullum CM, Biggs MM, Hester AL, Odegard TN, Carmack PS, Briggs RW, Haley RW. Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge. Radiology. 2011 Oct;261(1):218-25. doi: 10.1148/radiol.11101715. Epub 2011 Sep 13.
citation: Liu P, Aslan S, Li X, Buhner DM, Spence JS, Briggs RW, Haley RW, Lu H. Perfusion deficit to cholinergic challenge in veterans with Gulf War Illness. Neurotoxicology. 2011 Mar;32(2):242-6. doi: 10.1016/j.neuro.2010.12.004. Epub 2010 Dec 13.
citation: Falvo MJ, Lindheimer JB, Serrador JM. Dynamic cerebral autoregulation is impaired in Veterans with Gulf War Illness: A case-control study. PLoS One. 2018 Oct 15;13(10):e0205393. doi: 10.1371/journal.pone.0205393. eCollection 2018.
citation: Joyner MJ, Casey DP. Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev. 2015 Apr;95(2):549-601. doi: 10.1152/physrev.00035.2013.
citation: Barnes JN. Sex-specific factors regulating pressure and flow. Exp Physiol. 2017 Nov 1;102(11):1385-1392. doi: 10.1113/EP086531. Epub 2017 Sep 2.
citation: Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke. 2000 Jul;31(7):1672-8. doi: 10.1161/01.str.31.7.1672.
citation: Coverdale NS, Gati JS, Opalevych O, Perrotta A, Shoemaker JK. Cerebral blood flow velocity underestimates cerebral blood flow during modest hypercapnia and hypocapnia. J Appl Physiol (1985). 2014 Nov 15;117(10):1090-6. doi: 10.1152/japplphysiol.00285.2014. Epub 2014 Jul 10.
citation: Berman SE, Rivera-Rivera LA, Clark LR, Racine AM, Keevil JG, Bratzke LC, Carlsson CM, Bendlin BB, Rowley HA, Blennow K, Zetterberg H, Asthana S, Turski P, Johnson SC, Wieben O. Intracranial Arterial 4D-Flow is Associated with Metrics of Brain Health and Alzheimer's Disease. Alzheimers Dement (Amst). 2015 Dec 1;1(4):420-428. doi: 10.1016/j.dadm.2015.09.005.
citation: Rivera-Rivera LA, Turski P, Johnson KM, Hoffman C, Berman SE, Kilgas P, Rowley HA, Carlsson CM, Johnson SC, Wieben O. 4D flow MRI for intracranial hemodynamics assessment in Alzheimer's disease. J Cereb Blood Flow Metab. 2016 Oct;36(10):1718-1730. doi: 10.1177/0271678X15617171. Epub 2015 Nov 25.
citation: White RF, Steele L, O'Callaghan JP, Sullivan K, Binns JH, Golomb BA, Bloom FE, Bunker JA, Crawford F, Graves JC, Hardie A, Klimas N, Knox M, Meggs WJ, Melling J, Philbert MA, Grashow R. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016 Jan;74:449-75. doi: 10.1016/j.cortex.2015.08.022. Epub 2015 Sep 25.
citation: Lucas KE, Armenian HK, Debusk K, Calkins HG, Rowe PC. Characterizing Gulf War Illnesses: neurally mediated hypotension and postural tachycardia syndrome. Am J Med. 2005 Dec;118(12):1421-7. doi: 10.1016/j.amjmed.2005.06.034. No abstract available.
citation: Haley RW, Vongpatanasin W, Wolfe GI, Bryan WW, Armitage R, Hoffmann RF, Petty F, Callahan TS, Charuvastra E, Shell WE, Marshall WW, Victor RG. Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med. 2004 Oct 1;117(7):469-78. doi: 10.1016/j.amjmed.2004.03.041.
citation: Peckerman A, LaManca JJ, Smith SL, Taylor A, Tiersky L, Pollet C, Korn LR, Hurwitz BE, Ottenweller JE, Natelson BH. Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness. Psychosom Med. 2000 Jul-Aug;62(4):509-16. doi: 10.1097/00006842-200007000-00009.
citation: Peckerman A, Dahl K, Chemitiganti R, LaManca JJ, Ottenweller JE, Natelson BH. Effects of posttraumatic stress disorder on cardiovascular stress responses in Gulf War veterans with fatiguing illness. Auton Neurosci. 2003 Oct 31;108(1-2):63-72. doi: 10.1016/S1566-0702(03)00155-3.
citation: Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, Noah DL, Barrett DH, Randall B, Herwaldt BL, Mawle AC, Reeves WC. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998 Sep 16;280(11):981-8. doi: 10.1001/jama.280.11.981.
citation: Steele L. Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000 Nov 15;152(10):992-1002. doi: 10.1093/aje/152.10.992.
citation: Fletcher GF, Ades PA, Kligfield P, Arena R, Balady GJ, Bittner VA, Coke LA, Fleg JL, Forman DE, Gerber TC, Gulati M, Madan K, Rhodes J, Thompson PD, Williams MA; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology, Council on Nutrition, Physical Activity and Metabolism, Council on Cardiovascular and Stroke Nursing, and Council on Epidemiology and Prevention. Exercise standards for testing and training: a scientific statement from the American Heart Association. Circulation. 2013 Aug 20;128(8):873-934. doi: 10.1161/CIR.0b013e31829b5b44. Epub 2013 Jul 22. No abstract available.
citation: Cook DB, O'Connor PJ, Lange G, Steffener J. Functional neuroimaging correlates of mental fatigue induced by cognition among chronic fatigue syndrome patients and controls. Neuroimage. 2007 May 15;36(1):108-22. doi: 10.1016/j.neuroimage.2007.02.033. Epub 2007 Mar 3.
citation: Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: pathogenetic role. Curr Pain Headache Rep. 2002 Aug;6(4):259-66. doi: 10.1007/s11916-002-0046-1.
citation: Schweinhardt P, Bushnell MC. Pain imaging in health and disease--how far have we come? J Clin Invest. 2010 Nov;120(11):3788-97. doi: 10.1172/JCI43498. Epub 2010 Nov 1.
citation: Barnes JN, Hart EC, Curry TB, Nicholson WT, Eisenach JH, Wallin BG, Charkoudian N, Joyner MJ. Aging enhances autonomic support of blood pressure in women. Hypertension. 2014 Feb;63(2):303-8. doi: 10.1161/HYPERTENSIONAHA.113.02393. Epub 2013 Dec 9.
citation: Joyner MJ, Wallin BG, Charkoudian N. Sex differences and blood pressure regulation in humans. Exp Physiol. 2016 Mar;101(3):349-55. doi: 10.1113/EP085146. Epub 2015 Aug 16.
citation: Barnes JN, Harvey RE, Eisenmann NA, Miller KB, Johnson MC, Kruse SM, Lahr BD, Joyner MJ, Miller VM. Cerebrovascular reactivity after cessation of menopausal hormone treatment. Climacteric. 2019 Apr;22(2):182-189. doi: 10.1080/13697137.2018.1538340. Epub 2019 Jan 21.
citation: MacLeod CM. Half a century of research on the Stroop effect: an integrative review. Psychol Bull. 1991 Mar;109(2):163-203. doi: 10.1037/0033-2909.109.2.163. No abstract available.
citation: Lucas SJ, Ainslie PN, Murrell CJ, Thomas KN, Franz EA, Cotter JD. Effect of age on exercise-induced alterations in cognitive executive function: relationship to cerebral perfusion. Exp Gerontol. 2012 Aug;47(8):541-51. doi: 10.1016/j.exger.2011.12.002. Epub 2012 Jan 2.
citation: McMillan KM, Laird AR, Witt ST, Meyerand ME. Self-paced working memory: validation of verbal variations of the n-back paradigm. Brain Res. 2007 Mar 30;1139:133-42. doi: 10.1016/j.brainres.2006.12.058. Epub 2006 Dec 23.
citation: Jaeggi SM, Schmid C, Buschkuehl M, Perrig WJ. Differential age effects in load-dependent memory processing. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2009;16(1):80-102. doi: 10.1080/13825580802233426. Epub 2008 Aug 5.
citation: Rickards CA, Johnson BD, Harvey RE, Convertino VA, Joyner MJ, Barnes JN. Cerebral blood velocity regulation during progressive blood loss compared with lower body negative pressure in humans. J Appl Physiol (1985). 2015 Sep 15;119(6):677-85. doi: 10.1152/japplphysiol.00127.2015. Epub 2015 Jul 2.
citation: Committee on Gulf War and Health: Treatment for Chronic Multisymptom Illness; Board on the Health of Select Populations; Institute of Medicine. Gulf War and Health: Treatment for Chronic Multisymptom Illness. Washington (DC): National Academies Press (US); 2013 Apr 4. Available from http://www.ncbi.nlm.nih.gov/books/NBK206744/