Lymphatic System Health in Alzheimer's Disease

Summary

This study hopes to investigate differences in lymphatic health of patients with Alzheimer's disease by analyzing diffusion-weight images in conscious and sleep states. Dexmedetomidine is a short-acting agent that facilitates a sedated state characterized by slow waves and inhibition of norepinephrine. Conceptually, dexmedetomidine may be preferred to other agents, because it is a short-acting norepinephrine blocker, which could mimic slow wave sleep architecture, opening interstitial spaces, and facilitating plaque removal. Dexmedetomidine may also be preferred given its safety profile among the elderly and acutely ill compared to other anesthetic agents. Sleep will be induced with dexmedetomidine, and interstitial fluid convection will be assessed by measuring free-water diffusion imaging. Freewater diffusion imaging separates out the contributions of extracellular free water and water in the vicinity of cellular tissue; it is used to evaluate abnormalities in extracellular space, such as neuroinflammation, which may contribute to long-term cellular degeneration. This method of analysis could be useful in assessing the lymph systems ability to remove extracellular debris.

Timeline

Start

2021-12-10

Primary completion

2022-12-10

Completion

2023-12

Publications

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• Background Leshchyns'ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, Ittner LM, Sytnyk V. Abeta-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nat Commun. 2015 Nov 27;6:8836. doi: 10.1038/ncomms9836.
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• Background de Andres I, Garzon M, Reinoso-Suarez F. Functional Anatomy of Non-REM Sleep. Front Neurol. 2011 Nov 15;2:70. doi: 10.3389/fneur.2011.00070. eCollection 2011.
• Background Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.
• Background Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014 Dec;76(6):845-61. doi: 10.1002/ana.24271. Epub 2014 Sep 26.
• Background Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP. beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015 Jul;18(7):1051-7. doi: 10.1038/nn.4035. Epub 2015 Jun 1.
• Background Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain. 2014 Oct;137(Pt 10):2847-61. doi: 10.1093/brain/awu222. Epub 2014 Aug 20.
• Background Fitzgerald PJ. Is elevated norepinephrine an etiological factor in some cases of Alzheimer's disease? Curr Alzheimer Res. 2010 Sep;7(6):506-16. doi: 10.2174/156720510792231775.
• Background O'Donnell J, Ding F, Nedergaard M. Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator? Curr Sleep Med Rep. 2015 Mar;1(1):1-8. doi: 10.1007/s40675-014-0004-6. Epub 2015 Jan 29.
• Background Plog BA, Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. Annu Rev Pathol. 2018 Jan 24;13:379-394. doi: 10.1146/annurev-pathol-051217-111018.
• Background Stefanis L. alpha-Synuclein in Parkinson's disease. Cold Spring Harb Perspect Med. 2012 Feb;2(2):a009399. doi: 10.1101/cshperspect.a009399.
• Background Shteamer JW, Dedhia RC. Sedative choice in drug-induced sleep endoscopy: A neuropharmacology-based review. Laryngoscope. 2017 Jan;127(1):273-279. doi: 10.1002/lary.26132. Epub 2016 Jul 1.
• Background Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev. 2015 Jan 6;1(1):CD010269. doi: 10.1002/14651858.CD010269.pub2.
• Background Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16.
• Background Seitz DP, Reimer CL, Siddiqui N. A review of epidemiological evidence for general anesthesia as a risk factor for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Dec 2;47:122-7. doi: 10.1016/j.pnpbp.2012.06.022. Epub 2012 Jul 4.
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