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Thromb Haemost 2015; 114(06): 1230-1240
DOI: 10.1160/TH14-11-0938
Endothelium and Angiogenesis
Schattauer GmbH

Clinical significance of circulating vascular cell adhesion molecule-1 to white matter disintegrity in Alzheimer’s dementia

Chi-Wei Huang
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Meng-Han Tsai
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Nai-Ching Chen
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Wei-Hsi Chen
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Yan-Ting Lu
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Chun-Chung Lui
2   Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Ya-Ting Chang
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Wen-Neng Chang
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
,
Alice Y. W. Chang
3   Department of Physiology, National Cheng Kung University, Tainan, Taiwan
4   Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
,
Chiung-Chih Chang
1   Department of Neurology, Cognition and Aging Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
› Author Affiliations Financial support: This work was supported in part by grants CMRPG 8B1492 and CMRPG8C0572 from the Chang Gung Memorial Hospital and NSC 102–2314-B-182A-059 from the National Science Council to C. C.C and CMRPG8B1491 to C. W.H and CMRPG8C0571 to C. C. L.
Further Information

Publication History

Received: 16 November 2014

Accepted after major revision: 03 July 2015

Publication Date:
30 November 2017 (online)

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Summary

Endothelial dysfunction leads to worse cognitive performance in Alzheimer’s dementia (AD). While both cerebrovascular risk factors and endothelial dysfunction lead to activation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin, it is not known whether these biomarkers extend the diagnostic repertoire in reflecting intracerebral structural damage or cognitive performance. A total of 110 AD patients and 50 age-matched controls were enrolled. Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured and correlated with the cognitive performance, white matter macro-structural changes, and major tract-specific fractional anisotropy quantification. The AD patients were further stratified by clinical dementia rating score (mild dementia, n=60; moderate-to-severe dementia, n=50). Compared with the controls, plasma levels of VCAM-1 (p< 0.001), ICAM-1 (p=0.028) and E-selectin (p=0.016) were significantly higher in the patients, but only VCAM-1 levels significantly reflected the severity of dementia (p< 0.001). In addition, only VCAM-1 levels showed an association with macro- and micro- white matter changes especially in the superior longitudinal fasciculus (p< 0.001), posterior thalamic radiation (p=0.002), stria terminalis (p=0.002) and corpus callosum (p=0.009), and were independent of, age and cortical volume. These tracts show significant association with MMSE, short term memory and visuospatial function. Meanwhile, while VCAM-1 level correlated significantly with short-term memory (p=0.026) and drawing (p=0.025) scores in the AD patients after adjusting for age and education, the significance disappeared after adjusting for global FA. Endothelial activation, especially VCAM-1, was of clinical significance in AD that reflects macro- and micro-structural changes and poor short term memory and visuospatial function.

Keywords

Alzheimer’s dementia - cell adhesion molecule-1 - white matter disease - magnetic resonance imaging
 

  • References

  • 1 Ott A, Breteler MM, van Harskamp F. et al. Prevalence of Alzheimer’s disease and vascular dementia: association with education. The Rotterdam study. Br Med J 1995; 310: 970-973.
    PubMedSearch in Google Scholar
  • 2 Cullen KM, Kocsi Z, Stone J. Microvascular pathology in the aging human brain: evidence that senile plaques are sites of microhaemorrhages. Neurobiol Aging 2006; 27: 1786-1796.
    CrossrefPubMedSearch in Google Scholar
  • 3 Huang CW, Chang WN, Lui CC. et al. Impacts of hyper-homocysteinemia and white matter hyper-intensity in Alzheimer’s disease patients with normal creati-nine: an MRI-based study with longitudinal follow-up. CurrAlzheimer Res 2010; 07: 527-533.
    PubMedSearch in Google Scholar
  • 4 Bailey TL, Rivara CB, Rocher AB. et al. The nature and effects of cortical micro-vascular pathology in aging and Alzheimer’s disease. Neurol Res 2004; 26: 573-578.
    CrossrefPubMedSearch in Google Scholar
  • 5 Breteler MM. Vascular involvement in cognitive decline and dementia. Epidemiologic evidence from the Rotterdam Study and the Rotterdam Scan Study. Ann NY Acad Sci 2000; 903: 457-465.
    PubMedSearch in Google Scholar
  • 6 de la Torre JC. Is Alzheimer’s disease a neurodegenerative or a vascular disorder?. Data, dogma, and dialectics. Lancet Neurol 2004; 03: 184-190.
    PubMedSearch in Google Scholar
  • 7 Tu MC, Huang CW, Chen NC. et al. Hyperhomocysteinemia in Alzheimer dementia patients and cognitive decline after 6 months follow-up period. Acta Neurol Taiwan 2010; 19: 168-177.
    PubMedSearch in Google Scholar
  • 8 Chang YT, Chang CC, Lin HS. et al. Montreal cognitive assessment in assessing clinical severity and white matter hyperintensity in Alzheimer’s disease with normal control comparison. Acta Neurol Taiwan 2012; 21: 64-73.
    PubMedSearch in Google Scholar
  • 9 Deppe M, Duning T, Mohammadi S. et al. Diffusion-tensor imaging at 3 T: detection of white matter alterations in neurological patients on the basis of normal values. Invest Radiol 2007; 42: 338-345.
    CrossrefPubMedSearch in Google Scholar
  • 10 Hoth KF, Haley AP, Gunstad J. et al. Elevated C-reactive protein is related to cognitive decline in older adults with cardiovascular disease. J Am Geriatr Soc 2008; 56: 1898-1903.
    CrossrefPubMedSearch in Google Scholar
  • 11 Wright CB, Sacco RL, Rundek T. et al. Interleukin-6 is associated with cognitive function: the Northern Manhattan Study. J Stroke Cerebrovasc Dis 2006; 15: 34-38.
    CrossrefPubMedSearch in Google Scholar
  • 12 Huang CW, Chang WN, Huang SH. et al. Impact of homocysteine on cortical perfusion and cognitive decline in mild Alzheimer’s dementia. Eur J Neurol 2013; 20: 1191-1197.
    CrossrefPubMedSearch in Google Scholar
  • 13 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101.
    PubMedSearch in Google Scholar
  • 14 Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115: 1285-1295.
    PubMedSearch in Google Scholar
  • 15 Hassan A, Hunt BJ, O’Sullivan M. et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain 2003; 126: 424-432.
    CrossrefPubMedSearch in Google Scholar
  • 16 Markus HS, Hunt B, Palmer K. et al. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke 2005; 36: 1410-1414.
    CrossrefPubMedSearch in Google Scholar
  • 17 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscl Thromb Vasc Biol 2007; 27: 2292-2301.
    CrossrefPubMedSearch in Google Scholar
  • 18 Zuliani G, Cavalieri M, Galvani M. et al. Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci 2008; 272: 164-170.
    CrossrefPubMedSearch in Google Scholar
  • 19 Rentzos M, Michalopoulou M, Nikolaou C. et al. Serum levels of soluble inter-cellular adhesion molecule-1 and soluble endothelial leukocyte adhesion molecule-1 in Alzheimer’s disease. J Geriatric Psych Neurol 2004; 17: 225-231.
    PubMedSearch in Google Scholar
  • 20 Nielsen HM, Londos E, Minthon L. et al. Soluble adhesion molecules and angiotensin-converting enzyme in dementia. Neurobiol Dis 2007; 26: 27-35.
    CrossrefPubMedSearch in Google Scholar
  • 21 Schleimer RP, Sterbinsky SA, Kaiser J. et al. IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol 1992; 148: 1086-1092.
    PubMedSearch in Google Scholar
  • 22 Verbeek MM, Otte-Holler I, Westphal JR. et al. Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer’s disease. Am J Pathol 1994; 144: 104-116.
    PubMedSearch in Google Scholar
  • 23 Alexander AL, Lee JE, Lazar M. et al. Diffusion tensor imaging of the brain. Neurotherapeutics 2007; 04: 316-329.
    CrossrefPubMedSearch in Google Scholar
  • 24 Hua K, Zhang J, Wakana S. et al. Tract probability maps in stereotaxic spaces: analyses of white matter anatomy and tract-specific quantification. Neuroimage 2008; 39: 336-347.
    CrossrefPubMedSearch in Google Scholar
  • 25 Fazekas F, Kapeller P, Schmidt R. et al. The relation of cerebral magnetic resonance signal hyperintensities to Alzheimer’s disease. J Neurol Sci 1996; 142: 121-125.
    CrossrefPubMedSearch in Google Scholar
  • 26 Morey RA, Petty CM, Xu Y. et al. A comparison of automated segmentation and manual tracing for quantifying hippocampal and amygdala volumes. NeuroImage 2009; 45: 855-866.
    CrossrefPubMedSearch in Google Scholar
  • 27 Sanchez-Madrid F, Gonzalez-Amaro R. Drugs, inflammation and cell adhesion receptors. Exp Opin Pharmacother 2001; 02: 3-17.
    CrossrefPubMedSearch in Google Scholar
  • 28 Rouhl RP, Damoiseaux JG, Lodder J. et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging 2012; 33: 1800-1806.
    CrossrefPubMedSearch in Google Scholar
  • 29 Koedam EL, Lauffer V, van der Vlies AE. et al. Early-versus late-onset Alzheimer’s disease: more than age alone. J Alzheimer Dis 2010; 19: 1401-1408.
    PubMedSearch in Google Scholar
  • 30 Chang CC, Chang YY, Chang WN. et al. Cognitive deficits in multiple system atrophy correlate with frontal atrophy and disease duration. Eur J Neurol 2009; 16: 1144-1150.
    CrossrefPubMedSearch in Google Scholar
  • 31 American psychiatric associations diagnostic and statistical manual of mental disorders, ed 4 (dsm-iv) american psychiatric association washington. 1994
    PubMedSearch in Google Scholar
  • 32 McKhann G, Drachman D, Folstein M. et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984; 34: 939-944.
    CrossrefPubMedSearch in Google Scholar
  • 33 Chang YT, Huang CW, Chang YH. et al. Amyloid burden in the hippocampus and default mode network: relationships with gray matter volume and cognitive performance in mild stage Alzheimer disease. Medicine 2015; 94: e763.
    CrossrefPubMedSearch in Google Scholar
  • 34 McMurray RW. Adhesion molecules in autoimmune disease. Semin Arthritis Rheuma 1996; 25: 215-233.
    PubMedSearch in Google Scholar
  • 35 Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002; 23: 482-486.
    CrossrefPubMedSearch in Google Scholar
  • 36 Gavin 3rd JR. New classification and diagnostic criteria for diabetes mellitus. Clin Cornerstone 1998; 01: 1-12.
    PubMedSearch in Google Scholar
  • 37 Chobanian AV, Bakris GL, Black HR. et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. J Am Med Assoc 2003; 289: 2560-2572.
    CrossrefPubMedSearch in Google Scholar
  • 38 Folstein MF, Folstein SE, McHugh PR. „Mini-mental state“. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189-198.
    CrossrefPubMedSearch in Google Scholar
  • 39 Teng EL, Hasegawa K, Homma A. et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994; 06: 45-58 discussion 62.
    CrossrefPubMedSearch in Google Scholar
  • 40 Del Bo R, Comi GP, Bresolin N. et al. The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down’s syndrome subjects. J Neurol Sci 1997; 145: 87-91.
    CrossrefPubMedSearch in Google Scholar
  • 41 de Leeuw FE, de Kleine M, Frijns CJ. et al. Endothelial cell activation is associated with cerebral white matter lesions in patients with cerebrovascular disease. Ann NY Acad Sci 2002; 977: 306-314.
    CrossrefPubMedSearch in Google Scholar
  • 42 de la Torre JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging 2000; 21: 331-342.
    CrossrefPubMedSearch in Google Scholar
  • 43 Borroni B, Volpi R, Martini G. et al. Peripheral blood abnormalities in Alzheimer disease: evidence for early endothelial dysfunction. Alzheimer Dis Assoc Disorders 2002; 16: 150-155.
    CrossrefPubMedSearch in Google Scholar
  • 44 Bilato C, Crow MT. Atherosclerosis and the vascular biology of aging. Aging 1996; 08: 221-234.
    PubMedSearch in Google Scholar
  • 45 Merat S, Fruebis J, Sutphin M. et al. Effect of aging on aortic expression of the vascular cell adhesion molecule-1 and atherosclerosis in murine models of atherosclerosis. J Gerontol A Biol Sci Med Sci 2000; 55: B85-94.
    CrossrefPubMedSearch in Google Scholar
  • 46 Hassan A, Hunt BJ, O’Sullivan M. et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain 2004; 127: 212-219.
    CrossrefPubMedSearch in Google Scholar
  • 47 Varela-Moreiras G, Murphy MM, Scott JM. Cobalamin, folic acid, and homo-cysteine. Nutr Rev 2009; 67 (Suppl. 01) S69-72.
    CrossrefPubMedSearch in Google Scholar
  • 48 Baro L, Fonolla J, Pena JL. et al. n-3 Fatty acids plus oleic acid and vitamin supplemented milk consumption reduces total and LDL cholesterol, homocysteine and levels of endothelial adhesion molecules in healthy humans. Clin Nutr 2003; 22: 175-182.
    CrossrefPubMedSearch in Google Scholar
  • 49 Marz W, Scharnagl H, Winkler K. et al. Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study. Circulation 2004; 110: 3068-3074.
    CrossrefPubMedSearch in Google Scholar
  • 50 Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 2002; 109: 813-836.
    CrossrefPubMedSearch in Google Scholar
  • 51 Garg N, Krishan P, Syngle A. Rosuvastatin improves endothelial dysfunction in ankylosing spondylitis. Clin Rheumatol 2015; 34: 1065-1071.
    CrossrefPubMedSearch in Google Scholar
  • 52 Pierpaoli C, Barnett A, Pajevic S. et al. Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture. NeuroImage 2001; 13: 1174-1185.
    PubMedSearch in Google Scholar
  • 53 Radanovic M, Pereira FR, Stella F. et al. White matter abnormalities associated with Alzheimer’s disease and mild cognitive impairment: a critical review of MRI studies. Exp Rev Neurotherap 2013; 13: 483-493.
    PubMedSearch in Google Scholar
  • 54 Vestergaard M, Madsen KS, Baare WF. et al. White matter microstructure in superior longitudinal fasciculus associated with spatial working memory performance in children. J Cogn Neurosci 2011; 23: 2135-2146.
    CrossrefPubMedSearch in Google Scholar
  • 55 Stebbins GT, Murphy CM. Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol 2009; 21: 39-49.
    CrossrefPubMedSearch in Google Scholar
  • 56 Forsberg A, Engler H, Almkvist O. et al. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 2008; 29: 1456-1465.
    CrossrefPubMedSearch in Google Scholar
  • 57 Hwang SJ, Ballantyne CM, Sharrett AR. et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 1997; 96: 4219-4225.
    CrossrefPubMedSearch in Google Scholar
  • 58 Mielke MM, Zandi PP, Sjogren M. et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 2005; 64: 1689-1695.
    CrossrefPubMedSearch in Google Scholar
  • 59 Kivipelto M, Helkala EL, Laakso MP. et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 2002; 137: 149-155.
    CrossrefPubMedSearch in Google Scholar
  • 60 Fassbender K, Bertsch T, Mielke O. et al. Adhesion molecules in cerebrovascular diseases. Evidence for an inflammatory endothelial activation in cerebral large-and small-vessel disease. Stroke 1999; 30: 1647-1650.
    PubMedSearch in Google Scholar