Isolated Erythrocyte Membrane Susceptibility to Photo-oxidative Stress in Alzheimer's Disease

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

High lipid peroxidation and altered antioxidant defenses have been frequently reported in Alzheimer's disease patients.

The purpose of this study is to investigate susceptibility to photo-oxidation of isolated erythrocyte membranes, in patients affected by Alzheimer's disease and age- and sex-matched, non demented subjects.

Condition or disease
Alzheimer Disease; Oxidative Stress; Adrenocortical Hyperfunction

Detailed Description:

The study hypothesis is that high lipid peroxidation and decreased antioxidant defenses characterize the natural history of Alzheimer's disease.

It will be evaluated the release of malondialdehyde (MDA) from ex-vivo photo-oxidized erythrocyte ghosts, through a very easy and convenient lab procedure for the preparation of erythrocyte membrane samples.

Isolated and purified red blood cell membranes will be in vitro exposed to oxidative stress by UV-B radiation. The extent of cell membrane damage will be quantified by the fluorometric determination of MDA.

Induction of oxidative stress through ultraviolet rays, unlike that obtained by chemical oxidizing agents, is fully controllable, since it produces effects only during irradiation. Moreover, using isolated erythrocyte membranes allows for a greater specificity in the evaluation of MDA produced, and reduces the amount of blood required for the assay.

A portion of the blood sample (500 µL) will be sent to the laboratory of Lipinutragen (spin-off of CNR- National Research Center Bologna, Italy) where an erythrocyte membrane lipidomic analysis will be performed for the characterization of membrane phospholipids, in order to determinate the different lipid components (saturated fatty acids, monounsaturated and polyunsaturated, trans fatty acids), each one characterized by a different oxidative reactivity.

Recently published papers showed a striking association between urinary excretion of cortisol and the increase of some markers of oxidative damage of DNA and RNA (in humans). This finding provides further support to the idea that chronic psychological stress, who is associated to hypercortisolemia, can lead to an acceleration of the aging process.

The brain is a major target of the effects of glucocorticoids (CCS). The harmful consequences of cortisol on the hippocampus (one of the first brain areas affected by Alzheimer's disease) are well known. Some studies showed inverse correlations between cortisol levels and neuropsychological performance in patients with depression, dementia as well as in people treated chronically with CCS.

Alzheimer's disease is associated with states of hypercortisolism. Nonetheless, so far, its correlation with the level of oxidative stress has not been studied. We will investigate the relationship between 24h excretion of urinary cortisol and the level of malondialdehyde, produced by isolated and purified red blood cell membranes, in vitro exposed to oxidative stress by UV-B radiation.

Study Design

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Observational
Estimated Enrollment :	50 participants
Observational Model:	Case-Control
Time Perspective:	Cross-Sectional
Official Title:	Isolated Erythrocyte Membrane Susceptibility to Photo-oxidative Stress in Patients Affected by Alzheimer's Disease and Healthy Controls
Study Start Date :	June 2015
Estimated Primary Completion Date :	May 2018
Estimated Study Completion Date :	September 2018

Groups and Cohorts

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Group/Cohort
Alzheimer's disease
Non demented subjects

Outcome Measures

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Malondialdehyde assay [ Time Frame: At the time of recruitment ]
   Isolated and purified red blood cell membranes will be in vitro exposed to oxidative stress by UV-B radiation. The extent of cell membrane damage will be quantified by the fluorometric determination of malondialdehyde.

Secondary Outcome Measures :

1. Relationship between urinary excretion of cortisol and levels of malondialdehyde [ Time Frame: At the time of recruitment ]
   Hyperactivity of the hypothalamic pituitary adrenal axis has been frequently described in Alzheimer's disease. Recently published work reported an association between high secretion of cortisol and oxidative stress. We will investigate the relationship between 24 h excretion of urinary cortisol and the level of malondialdehyde, produced by isolated and purified red blood cell membranes, in vitro exposed to oxidative stress by UV-B radiation.

Biospecimen Retention:   Samples With DNA

Whole blood

Eligibility Criteria

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Ages Eligible for Study:	50 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes
Sampling Method:	Probability Sample

Study Population

Patients meeting NINCDS-ADRDA criteria for Alzheimer's disease and age- / sex-matched elderly subjects without dementia, will be recruited from those referring neurologists or geriatricians on an outpatient basis

Criteria

Inclusion Criteria:

• Outpatients of both sexes diagnosed with Alzheimer's disease according to NINCDS-ADRDA criteria.
• Age and sex-matched elderly subjects without dementia.

Exclusion Criteria:

• Recent neoplasia (< 1 year)
• Vitamin B12 deficiency, positive serology for syphilis, thyroid function abnormalities considered to be significant by the care provider.
• Use of vitamin or mineral supplements.
• Diagnosis of malnutrition (based on body mass index and total protein levels)
• Metabolic syndrome or diabetes.
• Hormonal replacement therapy.
• Smoking
• Chronic inflammatory disease (e.g. rheumatoid arthritis) and any other acute illness.

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Raffaele Antonelli Incalzi, M.D.	+39-06-225411	r.antonelli@unicampus.it
Contact: Francesco Maria Serino, M.D. PhD	+39-06-6790695	info@doctorsinitaly.com

Locations

Italy
Policlinico Universitario Campus Bio-Medico	Recruiting
Rome, RM, Italy, 00128
Contact: Raffaele Antonelli Incalzi, M.D. +39-06-225411 r.antonelli@unicampus.it
Contact: Francesco Maria Serino, M.D. +39-06-225411 ext 9123 info@doctorsinitaly.com

Sponsors and Collaborators

Raffaele Antonelli Incalzi

Investigators

Principal Investigator:	Francesco Maria Serino, M.D. PhD	Doctors in Italy
Principal Investigator:	Chiara Fanali, PhD	University Campus Bio-Medico
Principal Investigator:	Laura Dugo, PhD	University Campus Bio-Medico
Principal Investigator:	Simone Grasso, PhD	University Campus Bio-Medico
Study Chair:	Ettore Bergamini, M.D.	University of Pisa
Principal Investigator:	Francesca Ursini, M.D.	University Campus Bio-Medico
Principal Investigator:	Fabrizio Vernieri, M.D.	University Campus Bio-Medico
Study Director:	Marina Dachà, BS.Pharm	University Campus Bio-Medico
Principal Investigator:	Silvia Bernardini, M.D.	University Campus Bio-Medico
Principal Investigator:	Valentina Pasqualetti, PhD	University Campus Bio-Medico

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

Mangialasche F, Polidori MC, Monastero R, Ercolani S, Camarda C, Cecchetti R, Mecocci P. Biomarkers of oxidative and nitrosative damage in Alzheimer's disease and mild cognitive impairment. Ageing Res Rev. 2009 Oct;8(4):285-305. doi: 10.1016/j.arr.2009.04.002. Epub 2009 Apr 17. Review.

Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic Biol Med. 1997;23(1):134-47. Review.

Perry G, Nunomura A, Hirai K, Zhu X, Pérez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM, Takeda A, Smith MA. Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases? Free Radic Biol Med. 2002 Dec 1;33(11):1475-9. Review.

Mecocci P. Oxidative stress in mild cognitive impairment and Alzheimer disease: a continuum. J Alzheimers Dis. 2004 Apr;6(2):159-63. Review.

Polidori MC, Mecocci P. Plasma susceptibility to free radical-induced antioxidant consumption and lipid peroxidation is increased in very old subjects with Alzheimer disease. J Alzheimers Dis. 2002 Dec;4(6):517-22.

Galbusera C, Facheris M, Magni F, Galimberti G, Sala G, Tremolada L, Isella V, Guerini FR, Appollonio I, Galli-Kienle M, Ferrarese C. Increased susceptibility to plasma lipid peroxidation in Alzheimer disease patients. Curr Alzheimer Res. 2004 May;1(2):103-9.

Casado A, Encarnación López-Fernández M, Concepción Casado M, de La Torre R. Lipid peroxidation and antioxidant enzyme activities in vascular and Alzheimer dementias. Neurochem Res. 2008 Mar;33(3):450-8. Epub 2007 Aug 25.

Serra JA, Domínguez RO, de Lustig ES, Guareschi EM, Famulari AL, Bartolomé EL, Marschoff ER. Parkinson's disease is associated with oxidative stress: comparison of peripheral antioxidant profiles in living Parkinson's, Alzheimer's and vascular dementia patients. J Neural Transm (Vienna). 2001;108(10):1135-48.

Kawamoto EM, Munhoz CD, Glezer I, Bahia VS, Caramelli P, Nitrini R, Gorjão R, Curi R, Scavone C, Marcourakis T. Oxidative state in platelets and erythrocytes in aging and Alzheimer's disease. Neurobiol Aging. 2005 Jun;26(6):857-64.

Bermejo P, Gómez-Serranillos P, Santos J, Pastor E, Gil P, Martín-Aragón S. Determination of malonaldehyde in Alzheimer's disease: a comparative study of high-performance liquid chromatography and thiobarbituric acid test. Gerontology. 1997;43(4):218-22.

Baldeiras I, Santana I, Proença MT, Garrucho MH, Pascoal R, Rodrigues A, Duro D, Oliveira CR. Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer's disease. J Alzheimers Dis. 2008 Sep;15(1):117-28.

Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM, Moreira WL, Loureiro AP, de Souza-Talarico JN, Smid J, Porto CS, Bottino CM, Nitrini R, Barros SB, Camarini R, Marcourakis T. Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2011;26(1):59-68. doi: 10.3233/JAD-2011-110284.

Onaran I, Yalçin AS, Sultuybek G. Effect of donor age on the susceptibility of erythrocytes and erythrocyte membranes to cumene hydroperoxide-induced oxidative stress. Mech Ageing Dev. 1997 Nov;98(2):127-38.

García-Arumí E, Andreu AL, López-Hellín J, Schwartz S. Effect of oxidative stress on lymphocytes from elderly subjects. Clin Sci (Lond). 1998 Apr;94(4):447-52.

Davis KL, Davis BM, Greenwald BS, Mohs RC, Mathé AA, Johns CA, Horvath TB. Cortisol and Alzheimer's disease, I: Basal studies. Am J Psychiatry. 1986 Mar;143(3):300-5.

Costantini D, Marasco V, Møller AP. A meta-analysis of glucocorticoids as modulators of oxidative stress in vertebrates. J Comp Physiol B. 2011 May;181(4):447-56. doi: 10.1007/s00360-011-0566-2. Epub 2011 Mar 18. Review.

Joergensen A, Broedbaek K, Weimann A, Semba RD, Ferrucci L, Joergensen MB, Poulsen HE. Association between urinary excretion of cortisol and markers of oxidatively damaged DNA and RNA in humans. PLoS One. 2011;6(6):e20795. doi: 10.1371/journal.pone.0020795. Epub 2011 Jun 7.

Responsible Party:	Raffaele Antonelli Incalzi, Professor, Campus Bio-Medico University
ClinicalTrials.gov Identifier:	NCT01707719 History of Changes
Other Study ID Numbers:	ERASE
First Posted:	October 16, 2012
Last Update Posted:	March 15, 2018
Last Verified:	March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Raffaele Antonelli Incalzi, Campus Bio-Medico University:

Alzheimer's disease; Oxidative stress; HPA axis

Additional relevant MeSH terms:

Adrenal Gland Diseases; Alzheimer Disease; Disease Susceptibility; Adrenocortical Hyperfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases	Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Disease Attributes; Pathologic Processes; Endocrine System Diseases