Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.
ZahrNMKaufmanKLHarperCG.Clinical and pathological features of alcohol-related brain damage. Nat Rev Neurol2011;
7: 284–294.
2.
RaoRDraperB.Alcohol-related brain damage in older people. Lancet Psychiatry2015;
2: 674–675.
3.
VolkowNDWiersCEShokri-KojoriE, et al.
Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: studies with positron emission tomography. Neuropharmacology2017;
122: 175–188.
4.
LabissoWLRaulinACNwiduLL, et al.
The loss of alpha- and beta-tubulin proteins are a pathological hallmark of chronic alcohol consumption and natural brain ageing. Brain Sci2018;
8: 175–196.
5.
EhrlichDHumpelC.Effects of ethanol on aggregation, serotonin release, and amyloid precursor protein processing in rat and human platelets. Platelets2014;
25: 16–22.
6.
GongYSHuKYangLQ, et al.
Comparative effects of EtOH consumption and thiamine deficiency on cognitive impairment, oxidative damage, and beta-amyloid peptide overproduction in the brain. Free Radic Biol Med2017;
108: 163–173.
7.
WardlawJMBenvenisteHNedergaardM, et al.
Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol2020;
16: 137–153.
8.
LouveauASmirnovIKeyesTJ, et al.
Structural and functional features of central nervous system lymphatic vessels. Nature2015;
523: 337–341.
9.
PlogBANedergaardM.The glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol2018;
13: 379–394.
10.
LouveauAPlogBAAntilaS, et al.
Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest2017;
127: 3210–3219.
11.
YuLHuXLiH, et al.
Perivascular spaces, glymphatic system and MR. Front Neurol2022;
13: 844938.
12.
IneichenBVOkarSVProulxST, et al.
Perivascular spaces and their role in neuroinflammation. Neuron2022;
110: 3566–3581.
13.
BrownRBenvenisteHBlackSE, et al.
Understanding the role of the perivascular space in cerebral small vessel disease. Cardiovasc Res2018;
114: 1462–1473.
14.
RamaswamySKhasiyevFGutierrezJ.Brain enlarged perivascular spaces as imaging biomarkers of cerebrovascular disease: a clinical narrative review. J Am Heart Assoc2022;
11: e026601.
15.
ChengYMaXBelfieldKD, et al.
Biphasic effects of ethanol exposure on waste metabolites clearance in the CNS. Mol Neurobiol2021;
58: 3953–3967.
16.
LiuQYanLHuangM, et al.
Experimental alcoholism primes structural and functional impairment of the glymphatic pathway. Brain Behav Immun2020;
85: 106–119.
17.
MestreHHablitzLMXavierAL, et al.
Aquaporin-4-dependent glymphatic solute transport in the rodent brain. Elife2018;
7: e40070–e40101.
18.
WangMLYuMMWeiXE, et al.
Association of enlarged perivascular spaces with abeta and tau deposition in cognitively normal older population. Neurobiol Aging2021;
100: 32–38.
19.
YouMArteelGE.Effect of ethanol on lipid metabolism. J Hepatol2019;
70: 237–248.
20.
van der GaagMvan TolAVermuntS, et al.
Alcohol consumption stimulates early steps in reverse cholesterol transport. J Lipid Res2001;
42: 2077–2083.
21.
MendelsonJMelloN.Alcohol-induced hyperlipidemia and beta lipoproteins. Science (New York, N.Y.)1973;
180: 1372–1374.
22.
FarrSAYamadaKAButterfieldDA, et al.
Obesity and hypertriglyceridemia produce cognitive impairment. Endocrinology2008;
149: 2628–2636.
23.
PanzaFSolfrizziVD'IntronoA, et al.
Higher total cholesterol, cognitive decline, and dementia. Neurobiol Aging2009;
30: 546–548.
24.
KweeRKweeT.Virchow-Robin spaces at MR imaging. Radiographics2007;
27: 1071–1086.
25.
RaoRTopiwalaA.Alcohol use disorders and the brain. Addiction2020;
115: 1580–1589.
26.
ChenKLXuYChuAQ, et al.
Validation of the Chinese version of Montreal cognitive assessment basic for screening mild cognitive impairment. J Am Geriatr Soc2016;
64: e285–e290.
27.
HuangLChenKLLinBY, et al.
Chinese version of Montreal cognitive assessment basic for discrimination among different severities of Alzheimer's disease. Neuropsychiatr Dis Treat2018;
14: 2133–2140.
28.
GrundySMCleemanJIDanielsSR, et al.
Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation2005;
112: 2735–2752.
29.
HuangYZhangLWangZ, et al.
The prevalence and characteristics of metabolic syndrome according to different definitions in China: a nationwide cross-sectional study, 2012-2015. BMC Public Health2022;
22: 1869.
30.
WangJTianYQinC, et al.
Impaired glymphatic drainage underlying obstructive sleep apnea is associated with cognitive dysfunction. J Neurol2023;
270: 2204–2216.
31.
JungreisCAKanalEHirschWL, et al.
Normal perivascular spaces mimicking lacunar infarction: MR imaging. Radiology1988;
169: 101–104.
32.
RamirezJBerberianSABreenDP, et al.
Small and large magnetic resonance imaging-visible perivascular spaces in the basal ganglia of Parkinson's disease patients. Mov Disord2022;
37: 1304–1309.
33.
PotterGMDoubalFNJacksonCA, et al.
Enlarged perivascular spaces and cerebral small vessel disease. Int J Stroke2015;
10: 376–381.
34.
LambertCBenjaminPZeestratenE, et al.
Longitudinal patterns of leukoaraiosis and brain atrophy in symptomatic small vessel disease. Brain2016;
139: 1136–1151.
35.
BenjaminPZeestratenELambertC, et al.
Progression of MRI markers in cerebral small vessel disease: sample size considerations for clinical trials. J Cereb Blood Flow Metab2016;
36: 228–240.
36.
KressBIliffJXiaM, et al.
Impairment of paravascular clearance pathways in the aging brain. Ann Neurol2014;
76: 845–861.
37.
DingXWangXXiaD, et al.
Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson's disease. Nat Med2021;
27: 411–418.
38.
XieY-DZhaoC-QWangJ-P, et al.
Alcohol consumption analysis among patients with liver disease in China. Chin Med J (Engl)2019;
132: 420–430.
39.
SimhaV.Management of hypertriglyceridemia. BMJ2020;
371: m3109.
40.
Fernandez-SolaJ.Cardiovascular risks and benefits of moderate and heavy alcohol consumption. Nat Rev Cardiol2015;
12: 576–587.
41.
IliffJJWangMLiaoY, et al.
A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med2012;
4: 147ra111.
42.
FergusonSBlaneAPerrosP, et al.
Cognitive ability and brain structure in type 1 diabetes: relation to microangiopathy and preceding severe hypoglycemia. Diabetes2003;
52: 149–156.
43.
ZhuYCDufouilCSoumareA, et al.
High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia. JAD2010;
22: 663–672.
44.
PatankarTMitraDVarmaA, et al.
Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. Am J Neuroradiol2005;
26: 1512–1520.
45.
FrancisFBalleriniLWardlawJM.Perivascular spaces and their associations with risk factors, clinical disorders and neuroimaging features: a systematic review and meta-analysis. Int J Stroke2019;
14: 359–371.
46.
RingstadGVatneholSASEidePK.Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain2017;
140: 2691–2705.
47.
EidePKValnesLMPrippAH, et al.
Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus. J Cereb Blood Flow Metab2020;
40: 1849–1858.
48.
WangZZhangYHuF, et al.
Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus. CNS Neurosci Ther2020;
26: 1230–1240.
49.
NestorSMRupsinghRBorrieM, et al.
Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database. Brain2008;
131: 2443–2454.
50.
HuangS-YZhangY-RGuoY, et al.
Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease. Alzheimers Dement2024;
19: 13789–13808.
51.
WangZYaoTSongZ.Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver. Alcohol Clin Exp Res2010;
34: 471–478.
52.
DimacheAMȘalaruDLSascăuR, et al.
The role of high triglycerides level in predicting cognitive impairment: a review of current evidence. Nutrients2021;
13: 2118–2131.
53.
BanksWAFarrSASalamehTS, et al.
Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance. Int J Obes (Lond)2018;
42: 391–397.
54.
IliffJJChenMJPlogBA, et al.
Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci2014;
34: 16180–16193.
55.
HambyMECoppolaGAoY, et al.
Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J Neurosci2012;
32: 14489–14510.
56.
JohnGRLeeSCSongX, et al.
IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia2005;
49: 161–176.
57.
JensenCJMassieADe KeyserJ.Immune players in the CNS: the astrocyte. J Neuroimmune Pharmacol2013;
8: 824–839.
58.
KrumbholzMTheilDDerfussT, et al.
BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med2005;
201: 195–200.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
