J Alzheimers Dis. 2015;44(4):1349-59. doi: 10.3233/JAD-142046.

Fatty acid profiles in demented patients: identification of hexacosanoic acid (C26:0) as a blood lipid biomarker of dementia.

Zarrouk A1, Riedinger JM2, Ahmed SH3, Hammami S3, Chaabane W4, Debbabi M3, Ben Ammou S5, Rouaud O6, Frih M4, Lizard G7, Hammami M3.
  • 1Laboratoire Nutrition, Aliments Fonctionnels et Santé Vasculaire, UR12ES05 Université de Monastir, Tunisia Equipe Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique EA 7270/Université de Bourgogne/INSERM, Dijon, France.
  • 2Centre de Lutte Contre le Cancer GF Leclerc, Dijon, France.
  • 3Laboratoire Nutrition, Aliments Fonctionnels et Santé Vasculaire, UR12ES05 Université de Monastir, Tunisia.
  • 4Service Neurologie, CHU Fattouma Bourguiba, Monastir, Tunisia.
  • 5Service Neurologie, CHU Sahloul, Sousse, Tunisia.
  • 6Service Neurologie, CHU de Dijon, Dijon, France.
  • 7Equipe Biochimie du Peroxysome, Inflammation et Métabolisme Lipidique EA 7270/Université de Bourgogne/INSERM, Dijon, France.

 

Abstract

BACKGROUND: Several lipid metabolism alterations have been described in the brain and plasma of Alzheimer’s disease (AD) patients, suggesting a relation between lipid metabolism alteration and dementia.

OBJECTIVE: We attempted to identify blood fatty acids as biomarkers of dementia.

METHODS: Fatty acid profiles were established using gas chromatography with or without mass spectrometry on matched plasma and red blood cells (RBCs) of demented patients diagnosed with AD, vascular dementia, or other dementia, and compared with a control group of elderly individuals. The severity of dementia was evaluated with the Mini-Mental State Examination test.

RESULTS: Fatty acid analysis showed significant variations of fatty acid levels in demented patients including AD patients. The highest plasma and RBC accumulation was found with hexacosanoic acid (C26:0). Our data also support that alterations of desaturase and elongase activities may contribute to cognitive dysfunction.

CONCLUSION: The variations of fatty acid levels and the accumulation of C26:0 in the plasma and RBCs highlight an alteration of fatty acid metabolism in demented patients and point toward possible peroxisomal dysfunction. It is suggested that C26:0 may constitute a convenient blood biomarker of dementia that could be useful in routine medical practice.

KEYWORDS: Dementia; fatty acid profiles; hexacosanoic acid (C26:0); lipid biomarkers; plasma; red blood cells

PMID: 25428249

 

Supplement

Currently, there are several arguments supporting that lipid metabolism dysfunctions may play critical roles in various degenerative diseases including non demyelinating and demyelinating diseases such as Alzheimer’disease (AD), Parkinson’s disease, X-linked adrenoleukodystrophy (X-ALD) and multiple sclerosis. Indeed, in these different pathologies abnormal levels of lipids (fatty acids, oxysterols, phospholipids) have often been reported in the plasma and cerebrospinal fluids of patients (1-5). The aim of these different lipidomic studies is to identify easy to use lipid biomarkers, especially blood biomarkers, which can permit a convenient followup of the evolution of the disease and of the efficiency of treatments in routine clinical practice. In addition, these biomarkers, which permit to reveal lipid metabolism dysfunctions at different levels of the metabolic pathways leading to cholesterol, fatty acids and phospholipids synthesis, are also of interest to identify potential new drug targets in major brain diseases where no efficient treatments are available. At the moment, the identification of CYP46A1 (leading to the generation of 24(S)-hydroxycholesterol) as a new drug target in AD has been mainly realized by a lipidomic approach (2). In the study realized by Zarrouk A. et al. on patients with AD, vascular dementia, and other forms of dementia versus healthy subjects in the same age range (6), we determined with gas chromatography (GC), and gas chromatography coupled with mass spectrometry set to the selected-ion monitoring mode (GC/MS-SIM), the fatty acid profile ((Monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) profiles) both in the plasma and on membranes of red blood cells (RBCs). The desaturation and elongation index were calculated (C16:1/C16:0 and C18:1/C18:0, Δ9 desaturation index; C18:3/C18:2, Δ6 desaturation index; C20:4/C20:3, Δ5 desaturation index; C24:1/C18:1 and C18:0/C16:0 elongation index). Since modifications of peroxisomal metabolism are suspected of contributing to the development of AD, several markers of peroxisomal metabolism were studied: very long chain fatty acids (VLCFA: C22:0, C24:0, C26:0), docosahexahenoic acid (DHA: C22:6 n-3), phytanic acid, and plasmalogen-C16:0. Altogether, our data provide evidences of altered fatty acids profiles and fatty acids metabolism in demented patients. They demonstrate an accumulation of several fatty acids in plasma and RBCs, most particularly C26:0, which suggests possible peroxisomal dysfunctions (7, 8), possibly a convenient blood biomarker of dementia that may be useful in routine medical practice.

 2015 04 26 Gérard LIZARD Amira Zarrouk Fig.1

Figure1: Lipid metabolism dysfunctions in Alzheimer’s disease and other dementia. In several major neurodegenerative diseases (including Alzheimer’s disease: AD), abnormal levels of several lipids (oxysterols, fatty acids, phospholipids) are often observed. Some of these lipids can constitute suitable lipid biomarkers of AD. It is expected that some of these lipid biomarkers, which highlight metabolic lipid dysfunctions in AD, will permit to identify new drug targets and to develop efficient treatments.

Altogether, our data bring new evidences supporting alterations of fatty acid metabolism, in patients with dementia, especially in AD. As abnormal levels of oxysterols and phospholipids, suggesting alterations of cholesterol and phospholipids metabolism are also reported by different authors, it is suggested that an important contribution of lipid dysfunctions could participate to the physiopathology of AD and other dementia (Figure 1). It is expected that a better knowledge on the relationships between amyloidogenesis, tauopathy, fatty acids, cholesterol, and phospholipids metabolism will permit to identify new and efficient therapeutic targets in major neurodegenerative diseases.
References

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3 Cunnane SC, Schneider JA, Tangney C, Tremblay-Mercier J, Fortier M, Bennett DA, Morris MC 2012 Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 29: 691-697.

4 Björkhem I, Lövgren-Sandblom A, Leoni V, Meaney S, Brodin L, Salveson L, Winge K, Pålhagen S, Svenningsson P 2013 Oxysterols and Parkinson’s disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease. Neurosci Lett 555:102-105.

5 Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH, Hall WJ, Fisher SG, Peterson DR, Haley JM, Nazar MD, Rich SA, Berlau DJ, Peltz CB, Tan MT, Kawas CH, Federoff HJ 2014 Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med 20: 415-418.

6 Zarrouk A, Riedinger JM, Ahmed SH, Hammami S, Chaabane W, Debbabi M, Ben Ammou S, Rouaud O, Frih M, Lizard G, Hammami M 2015 Fatty acid profiles in demented patients: identification of hexacosanoic acid (C26:0) as a blood lipid biomarker of dementia. J Alzheimers Dis 44: 1349-1359.

7 Kou J, Kovacs GG, Höftberger R, Kulik W, Brodde A, Forss-Petter S, Hönigschnabl S, Gleiss A, Brügger B, Wanders R, Just W, Budka H, Jungwirth S,Fischer P, Berger J 2011 Peroxisomal alterations in Alzheimer’s disease. Acta Neuropathol 122: 271-283.

8 Trompier D, Vejux A, Zarrouk A, Gondcaille C, Geillon F, Nury T, Savary S, Lizard G 2014 Brain peroxisomes. Biochimie 98: 102-110.

 

Contact

Dr. Gérard Lizard and Dr Amira Zarrouk, Laboratoire BIO-peroxIL–EA 7270 / INSERM, Faculté des Sciences Gabriel, 6 Bd Gabriel, 21000 Dijon, France ; Phone: +33 380396256; Fax: +33 380396250; E.mail: gerard.lizard@u-bourgogne.fr; zarroukamira@gmail.com

 

 

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