{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:38:28Z","timestamp":1784547508502,"version":"3.55.0"},"reference-count":56,"publisher":"Georg Thieme Verlag KG","issue":"01","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Plast Surg"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lymphedema has traditionally been viewed as a localized disorder characterized by regional fluid accumulation and tissue swelling. However, emerging evidence challenges this paradigm, revealing that lower limb lymphedema induces significant systemic pathophysiological changes. This review synthesizes recent findings demonstrating that lymphedema triggers widespread oxidative stress, chronic inflammation, dysregulated gene expression in circulating monocytes, and contralateral limb muscle edema\u2014even in the absence of clinical lymphedema in the unaffected limb. Furthermore, we examine the potential association between lymphedema and increased Alzheimer's disease (AD) risk through shared mechanisms involving oxidative stress and neuroinflammation. Lymphaticovenous anastomosis (LVA), a minimally invasive supermicrosurgical technique, has emerged as an effective intervention that not only reduces limb volume but also reverses many of these systemic alterations. Studies utilizing advanced imaging techniques, including magnetic resonance volumetry and diffusion tensor imaging, combined with comprehensive biomarker analyses, have documented post-LVA improvements in antioxidant capacity, reduction in oxidative stress markers, normalization of inflammatory cytokines, recovery of dysregulated gene expression patterns, and decreased muscle edema bilaterally. Additionally, preliminary data suggest LVA may reduce AD biomarkers, including tau protein and amyloid-beta levels, while increasing neuroprotective factors such as brain-derived neurotrophic factor. These findings fundamentally redefine lymphedema as a systemic condition with far-reaching metabolic and potentially neurodegenerative consequences, positioning LVA as a therapeutic intervention with benefits extending beyond local symptom control to systemic disease modification.<\/jats:p>","DOI":"10.1055\/a-2780-1561","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:02:57Z","timestamp":1768953777000},"page":"097-102","source":"Crossref","is-referenced-by-count":1,"title":["From Limb to Brain: Lymphedema as a Systemic Disease with Metabolic, Immunological, and Neurodegenerative Consequences and the Disease-Modifying Potential of Lymphaticovenous Anastomosis\u2014An Integrative Analysis"],"prefix":"10.1055","volume":"40","author":[{"given":"Johnson Chia-Shen","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Plastic and Reconstructive Surgery, Department of Surgery, Lymphedema Center, Kaohsiung Chang Gung Memorial Hospital, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1196\/annals.1413.014","article-title":"Estimating the population burden of lymphedema","volume":"1131","author":"S G Rockson","year":"2008","journal-title":"Ann N Y Acad Sci"},{"issue":"02","key":"ref2","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1136\/ijgc-2019-001032","article-title":"Lower extremity lymphedema in patients with gynecologic malignancies","volume":"30","author":"K Dessources","year":"2020","journal-title":"Int J Gynecol Cancer"},{"issue":"06","key":"ref3","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.jaad.2017.03.022","article-title":"Lymphedema: pathophysiology and clinical manifestations","volume":"77","author":"A A Grada","year":"2017","journal-title":"J Am Acad Dermatol"},{"issue":"02","key":"ref4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1089\/lrb.2021.29103.sr","article-title":"Lymphedema, inflammation, and fat","volume":"19","author":"S G Rockson","year":"2021","journal-title":"Lymphat Res Biol"},{"issue":"09","key":"ref5","doi-asserted-by":"crossref","first-page":"H1065","DOI":"10.1152\/ajpheart.00598.2014","article-title":"Regulation of inflammation and fibrosis by macrophages in lymphedema","volume":"308","author":"S Ghanta","year":"2015","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"05","key":"ref6","doi-asserted-by":"crossref","first-page":"573","DOI":"10.3109\/13880209.2012.749923","article-title":"The role of cyclooxygenase-derived oxidative stress in surgically induced lymphedema in a mouse tail model","volume":"51","author":"T C Chang","year":"2013","journal-title":"Pharm Biol"},{"issue":"12","key":"ref7","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1093\/qjmed\/95.12.803","article-title":"Oxidative stress in chronic lymphoedema","volume":"95","author":"W G Siems","year":"2002","journal-title":"QJM"},{"issue":"01","key":"ref8","first-page":"8","article-title":"[Increased formation of free radicals in chronic lymphedema]","volume":"18","author":"A Beier","year":"1994","journal-title":"Z Lymphol"},{"issue":"05","key":"ref9","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1097\/PRS.0000000000006169","article-title":"Supermicrosurgical lymphaticovenous anastomosis as an alternative treatment option for patients with lymphorrhea","volume":"144","author":"J C Yang","year":"2019","journal-title":"Plast Reconstr Surg"},{"issue":"11","key":"ref10","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1002\/bjs.9588","article-title":"Lymphaticovenular anastomosis to prevent cellulitis associated with lymphoedema","volume":"101","author":"M Mihara","year":"2014","journal-title":"Br J Surg"},{"issue":"06","key":"ref11","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1055\/s-2006-947150","article-title":"Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphedema in the upper extremities","volume":"16","author":"I Koshima","year":"2000","journal-title":"J Reconstr Microsurg"},{"issue":"02","key":"ref12","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.jamcollsurg.2019.10.007","article-title":"Supermicrosurgical lymphaticovenous anastomosis as an alternative treatment option for moderate-to-severe lower limb lymphedema","volume":"230","author":"J C Yang","year":"2020","journal-title":"J Am Coll Surg"},{"issue":"01","key":"ref13","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/PRS.0000000000007507","article-title":"Changing the paradigm: lymphovenous anastomosis in advanced stage lower extremity lymphedema","volume":"147","author":"H G Cha","year":"2021","journal-title":"Plast Reconstr Surg"},{"issue":"05","key":"ref14","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/S1474-4422(23)00038-8","article-title":"Chronic effects of inflammation on tauopathies","volume":"22","author":"C Langworth-Green","year":"2023","journal-title":"Lancet Neurol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"796867","DOI":"10.3389\/fimmu.2021.796867","article-title":"The impact of systemic inflammation on Alzheimer's disease pathology","volume":"12","author":"J Xie","year":"2022","journal-title":"Front Immunol"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"101619","DOI":"10.1016\/j.arr.2022.101619","article-title":"Oxidative stress: the core pathogenesis and mechanism of Alzheimer's disease","volume":"77","author":"R Bai","year":"2022","journal-title":"Ageing Res Rev"},{"issue":"03","key":"ref17","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"D A Butterfield","year":"2019","journal-title":"Nat Rev Neurosci"},{"key":"ref18","first-page":"2638703","article-title":"Oxidative stress and dementia in Alzheimer's patients: effects of synbiotic supplementation","volume":"2020","author":"A MM Ton","year":"2020","journal-title":"Oxid Med Cell Longev"},{"issue":"23","key":"ref19","first-page":"e2340","article-title":"DNA methylation and protein markers of chronic inflammation and their associations with brain and cognitive aging","volume":"97","author":"E LS Conole","year":"2021","journal-title":"Neurology"},{"issue":"07","key":"ref20","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1371\/journal.pmed.0030254","article-title":"Inflammatory manifestations of experimental lymphatic insufficiency","volume":"3","author":"R Tabibiazar","year":"2006","journal-title":"PLoS Med"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"732415","DOI":"10.3389\/fcell.2021.732415","article-title":"Crosstalk between microRNAs and the pathological features of secondary lymphedema","volume":"9","author":"K M Yusof","year":"2021","journal-title":"Front Cell Dev Biol"},{"issue":"01","key":"ref22","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1080\/01635581.2019.1616781","article-title":"The effects of synbiotic supplementation on antioxidant capacity and arm volumes in survivors of breast cancer-related lymphedema","volume":"72","author":"M Navaei","year":"2020","journal-title":"Nutr Cancer"},{"issue":"07","key":"ref23","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.3390\/jcm10071540","article-title":"Lymphaticovenous anastomosis supermicrosurgery decreases oxidative stress and increases antioxidant capacity in the serum of lymphedema patients","volume":"10","author":"J C-S Yang","year":"2021","journal-title":"J Clin Med"},{"issue":"07","key":"ref24","doi-asserted-by":"crossref","first-page":"e6955","DOI":"10.1097\/GOX.0000000000006955","article-title":"Linking lymphedema, chronic inflammation, oxidative stress, Alzheimer disease, and potential role of lymphaticovenous anastomosis","volume":"13","author":"J C-S Yang","year":"2025","journal-title":"Plast Reconstr Surg Glob Open"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"761","DOI":"10.2147\/JIR.S350421","article-title":"Recovery of dysregulated genes in cancer-related lower limb lymphedema after supermicrosurgical lymphaticovenous anastomosis\u2014a prospective longitudinal cohort study","volume":"15","author":"J C-S Yang","year":"2022","journal-title":"J Inflamm Res"},{"issue":"02","key":"ref26","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.atherosclerosis.2012.12.030","article-title":"Expression pattern in human macrophages dependent on 9p21.3 coronary artery disease risk locus","volume":"227","author":"C Zollbrecht","year":"2013","journal-title":"Atherosclerosis"},{"issue":"08","key":"ref27","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1210\/me.2010-0010","article-title":"GPR103b functions in the peripheral regulation of adipogenesis","volume":"24","author":"M Mulumba","year":"2010","journal-title":"Mol Endocrinol"},{"issue":"06","key":"ref28","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1172\/JCI122256","article-title":"FoxO3 activation in hypoxic tubules prevents chronic kidney disease","volume":"129","author":"L Li","year":"2019","journal-title":"J Clin Invest"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"642547","DOI":"10.3389\/fonc.2021.642547","article-title":"The role of the transcription factor EGR1 in cancer","volume":"11","author":"B Wang","year":"2021","journal-title":"Front Oncol"},{"issue":"03","key":"ref30","doi-asserted-by":"crossref","first-page":"E317","DOI":"10.1073\/pnas.1614684114","article-title":"Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling","volume":"114","author":"A M Kidger","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"05","key":"ref31","doi-asserted-by":"crossref","first-page":"101081","DOI":"10.1016\/j.psj.2021.101081","article-title":"Expression analysis of genes related to lipid metabolism in peripheral blood lymphocytes of chickens challenged with reticuloendotheliosis virus","volume":"100","author":"Y Bi","year":"2021","journal-title":"Poult Sci"},{"issue":"04","key":"ref32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1089\/lrb.2006.4404","article-title":"Adipose tissue dominates chronic arm lymphedema following breast cancer: an analysis using volume rendered CT images","volume":"4","author":"H Brorson","year":"2006","journal-title":"Lymphat Res Biol"},{"issue":"06","key":"ref33","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1139\/cjpp-2020-0448","article-title":"FoxO3 transcription factor promotes autophagy after oxidative stress injury in HT22 cells","volume":"99","author":"A Deng","year":"2021","journal-title":"Can J Physiol Pharmacol"},{"issue":"10","key":"ref34","doi-asserted-by":"crossref","first-page":"e135454","DOI":"10.1172\/jci.insight.135454","article-title":"Tubular \u03b2-catenin and FoxO3 interactions protect in chronic kidney disease","volume":"5","author":"S Nlandu-Khodo","year":"2020","journal-title":"JCI Insight"},{"issue":"02","key":"ref35","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/XCS.0000000000000236","article-title":"Effect of lymphaticovenous anastomosis on muscle edema, limb, and subfascial volume in lower limb lymphedema: MRI studies","volume":"235","author":"J C-S Yang","year":"2022","journal-title":"J Am Coll Surg"},{"issue":"03","key":"ref36","doi-asserted-by":"crossref","first-page":"E56","DOI":"10.1148\/rg.343125062","article-title":"Diffusion tensor imaging in musculoskeletal disorders","volume":"34","author":"J F Budzik","year":"2014","journal-title":"Radiographics"},{"issue":"02","key":"ref37","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/mrm.20953","article-title":"DTI-based assessment of ischemia-reperfusion in mouse skeletal muscle","volume":"56","author":"A M Heemskerk","year":"2006","journal-title":"Magn Reson Med"},{"issue":"01","key":"ref38","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1055\/s-0038-1635118","article-title":"Anatomy of the lymphatic system and the lymphosome concept with reference to lymphedema","volume":"32","author":"H Suami","year":"2018","journal-title":"Semin Plast Surg"},{"issue":"05","key":"ref39","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.3390\/cancers12051338","article-title":"Anatomical theories of the pathophysiology of cancer-related lymphoedema","volume":"12","author":"H Suami","year":"2020","journal-title":"Cancers (Basel)"},{"issue":"02","key":"ref40","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1002\/alz.12694","article-title":"Global estimates on the number of persons across the Alzheimer's disease continuum","volume":"19","author":"A Gustavsson","year":"2023","journal-title":"Alzheimers Dement"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"110995","DOI":"10.1016\/j.biopha.2020.110995","article-title":"Association between chronic stress and Alzheimer's disease: therapeutic effects of Saffron","volume":"133","author":"M Saeedi","year":"2021","journal-title":"Biomed Pharmacother"},{"issue":"05","key":"ref42","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1001\/jamaneurol.2018.4666","article-title":"Assessment of plasma total tau level as a predictive biomarker for dementia and related endophenotypes","volume":"76","author":"M P Pase","year":"2019","journal-title":"JAMA Neurol"},{"issue":"02","key":"ref43","doi-asserted-by":"crossref","first-page":"178","DOI":"10.14283\/jpad.2023.15","article-title":"Predictive utility of plasma amyloid and tau for cognitive decline in cognitively normal adults","volume":"10","author":"Y J Lee","year":"2023","journal-title":"J Prev Alzheimers Dis"},{"issue":"09","key":"ref44","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1001\/jamaneurol.2017.1359","article-title":"Association of plasma total tau level with cognitive decline and risk of mild cognitive impairment or dementia in the Mayo Clinic Study on Aging","volume":"74","author":"M M Mielke","year":"2017","journal-title":"JAMA Neurol"},{"issue":"03","key":"ref45","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/brain\/awy347","article-title":"Plasma tau\/amyloid-\u03b21-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer's disease","volume":"142","author":"J C Park","year":"2019","journal-title":"Brain"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3389\/fncel.2019.00363","article-title":"Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain","volume":"13","author":"M Miranda","year":"2019","journal-title":"Front Cell Neurosci"},{"issue":"03","key":"ref47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.3390\/ijms18030545","article-title":"More insight into BDNF against neurodegeneration: anti-apoptosis, anti-oxidation, and suppression of autophagy","volume":"18","author":"S D Chen","year":"2017","journal-title":"Int J Mol Sci"},{"issue":"01","key":"ref48","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40035-022-00279-0","article-title":"Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential","volume":"11","author":"L Gao","year":"2022","journal-title":"Transl Neurodegener"},{"issue":"23","key":"ref49","doi-asserted-by":"crossref","first-page":"14599","DOI":"10.3390\/ijms232314599","article-title":"Gene- and gender-related decrease in serum BDNF levels in Alzheimer's disease","volume":"23","author":"D Piancatelli","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"02","key":"ref50","doi-asserted-by":"crossref","first-page":"BSR20193629","DOI":"10.1042\/BSR20193629","article-title":"Peripheral inflammation promotes brain tau transmission via disrupting blood-brain barrier","volume":"40","author":"Y Liu","year":"2020","journal-title":"Biosci Rep"},{"issue":"10","key":"ref51","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1002\/alz.12341","article-title":"Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1\u03b2 drives amplified responses in primed astrocytes and neuronal network dysfunction","volume":"17","author":"A B Lopez-Rodriguez","year":"2021","journal-title":"Alzheimers Dement"},{"issue":"01","key":"ref52","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12974-023-02747-4","article-title":"IL-1\u03b2 and TNF-\u03b1 play an important role in modulating the risk of periodontitis and Alzheimer's disease","volume":"20","author":"R P Wang","year":"2023","journal-title":"J Neuroinflammation"},{"issue":"01","key":"ref53","doi-asserted-by":"crossref","first-page":"10","DOI":"10.5483\/BMBRep.2020.53.1.309","article-title":"Peripheral inflammatory biomarkers in Alzheimer's disease: a brief review","volume":"53","author":"J C Park","year":"2020","journal-title":"BMB Rep"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"105870","DOI":"10.1016\/j.psyneuen.2022.105870","article-title":"Peripheral inflammation marker relationships to cognition in healthy older adults - a systematic review","volume":"144","author":"M T Fard","year":"2022","journal-title":"Psychoneuroendocrinology"},{"issue":"01","key":"ref55","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s13024-023-00627-2","article-title":"The role of peripheral inflammatory insults in Alzheimer's disease: a review and research roadmap","volume":"18","author":"K A Walker","year":"2023","journal-title":"Mol Neurodegener"},{"issue":"04","key":"ref56","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1017\/S1041610218001126","article-title":"Peripheral inflammation in mild cognitive impairment with possible and probable Lewy body disease and Alzheimer's disease","volume":"31","author":"E King","year":"2019","journal-title":"Int Psychogeriatr"}],"container-title":["Seminars in Plastic Surgery"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2780-1561.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T22:36:53Z","timestamp":1777070213000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2780-1561"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":56,"journal-issue":{"issue":"01","published-online":{"date-parts":[[2026,4,24]]},"published-print":{"date-parts":[[2026,2]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2780-1561","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["1535-2188","1536-0067"],"issn-type":[{"value":"1535-2188","type":"print"},{"value":"1536-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}