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

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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 13 Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84: 2068-2101.
• 14 Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation 2007; 115: 1285-1295.
• 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.
• 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.
• 17 Galkina E, Ley K. Vascular adhesion molecules in atherosclerosis. Arterioscl Thromb Vasc Biol 2007; 27: 2292-2301.
• 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.
• 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.
• 20 Nielsen HM, Londos E, Minthon L. et al. Soluble adhesion molecules and angiotensin-converting enzyme in dementia. Neurobiol Dis 2007; 26: 27-35.
• 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.
• 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.
• 23 Alexander AL, Lee JE, Lazar M. et al. Diffusion tensor imaging of the brain. Neurotherapeutics 2007; 04: 316-329.
• 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.
• 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.
• 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.
• 27 Sanchez-Madrid F, Gonzalez-Amaro R. Drugs, inflammation and cell adhesion receptors. Exp Opin Pharmacother 2001; 02: 3-17.
• 28 Rouhl RP, Damoiseaux JG, Lodder J. et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging 2012; 33: 1800-1806.
• 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.
• 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.
• 31 American psychiatric associations diagnostic and statistical manual of mental disorders, ed 4 (dsm-iv) american psychiatric association washington. 1994
• 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.
• 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.
• 34 McMurray RW. Adhesion molecules in autoimmune disease. Semin Arthritis Rheuma 1996; 25: 215-233.
• 35 Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci 2002; 23: 482-486.
• 36 Gavin 3rd JR. New classification and diagnostic criteria for diabetes mellitus. Clin Cornerstone 1998; 01: 1-12.
• 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.
• 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.
• 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.
• 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.
• 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.
• 42 de la Torre JC. Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer’s pathogenesis. Neurobiol Aging 2000; 21: 331-342.
• 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.
• 44 Bilato C, Crow MT. Atherosclerosis and the vascular biology of aging. Aging 1996; 08: 221-234.
• 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.
• 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.
• 47 Varela-Moreiras G, Murphy MM, Scott JM. Cobalamin, folic acid, and homo-cysteine. Nutr Rev 2009; 67 (Suppl. 01) S69-72.
• 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.
• 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.
• 50 Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 2002; 109: 813-836.
• 51 Garg N, Krishan P, Syngle A. Rosuvastatin improves endothelial dysfunction in ankylosing spondylitis. Clin Rheumatol 2015; 34: 1065-1071.
• 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.
• 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.
• 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.
• 55 Stebbins GT, Murphy CM. Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol 2009; 21: 39-49.
• 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.
• 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.
• 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.
• 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.
• 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.