Atherosclerosis 206 (2009) 309–313 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: A correlation study in patients with cognitive impairment Gaetano Gorgone a,b , Francesca Ursini a , Claudia Altamura a,b , Federica Bressi a , Mario Tombini a , Giuseppe Curcio a,c , Paola Chiovenda a,b , Rosanna Squitti b , Mauro Silvestrini d , Riccardo Ientile e , Francesco Pisani f , Paolo Maria Rossini a,c , Fabrizio Vernieri a,b,∗ a Neurologia Clinica, Università Campus Bio-Medico, Roma, Italy b Associazione Fatebenefratelli per la Ricerca AFaR: Dipartimento di Neuroscienze, Ospedale ‘San Giovanni Calibita’ Fatebenefratelli, Isola Tiberina, Roma, Italy c Casa di Cura San Raffaele Cassino, Cassino Italy d Clinica Neurologica, Università Politecnica delle Marche, Ancona, Italy e Dipartimento di Scienze Biochimiche, Fisiologiche e della Nutrizione, Università di Messina, Messina, Italy f I Clinica Neurologica, Università di Messina, Messina, Italy article info Article history: Received 31 July 2008 Received in revised form 3 February 2009 Accepted 18 February 2009 Available online 11 March 2009 Keywords: Alzheimer disease Intima-media thickness IMT Homocysteine MTHFR abstract Objective: Intima-media thickness (IMT) seems associated with risk of Alzheimer disease (AD). Homo- cysteine (hcy) is a risk factor for vascular diseases and dementia. This study aimed at investigating the possible relationship among IMT, plasma hcy and C677T methylentetrahydrofolate reductase (MTHFR) polymorphism in relation to cognitive status. Methods: Sixty-three patients with cognitive impairment and 64 controls underwent biochemical, neu- ropsychological and carotid ultrasound assessment. Results: After age and folate adjustment, plasma hcy correlated with both Mini Mental State Examination (MMSE) score (r = -0.7, p < 0.01) and IMT (r = 0.7, p < 0.01). Among patients with cognitive impairment, carriers of TT677 MTHFR genotype had plasma hcy (p < 0.001) and IMT (p < 0.01) values higher than non carriers. Furthermore, multiple regression analysis showed that MMSE scores were associated with plasma hcy (ˇ = -0.3, p = 0.01), IMT (ˇ = -0.3, p = 0.01) and TT677 MTHFR genotype (ˇ = -0.3, p = 0.02). Structural equa- tion modelling showed that the relation between hcy levels and MMSE score was partly direct (parameter estimate = -0.6; p = 0.01) and partly mediated by IMT values (parameter estimate = -0.4; p = 0.03). Finally, IMT resulted associated with hypertension (parameter estimate = 0.8; p < 0.0001). Conclusion: Our findings suggest that TT677 MTHFR genotype promotes plasma homocysteine increase which in turn may favour intima-media thickening in patients with cognitive impairment. Hcy may promote neuronal damage through multiple mechanisms, including a micro-vascular damage, mediated by IMT increase, and a direct neuro-toxic effect. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Atherosclerosis is a risk factor for both vascular dementia and Alzheimer disease (AD) [1,2]. Cross-sectional and case-control stud- ies demonstrated that, among other vascular risk factors, elevated plasma levels of homocysteine (hcy) are associated to AD suscep- tibility [3]. Additionally, in non-demented elderly population, hcy plasma levels are inversely associated with global cognitive perfor- mances and specific cognitive skills [4]. ∗ Corresponding author at: Neurologia Clinica, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, Roma 00128, Italy. Tel.: +39 06 225411285; fax: +39 06 225411955. E-mail address: f.vernieri@unicampus.it (F. Vernieri). Homocysteine results from de-methylation of the S-adenosil- methionine [5]; metabolism of hcy converting into methionine occurs via one of two re-methylation cycles, whose rate-limiting enzymes are methylenetetrahydrofolate reductase (MTHFR) and betaine hcy methyltransferase. Alternatively, hcy can be metabo- lized to cysteine via cystathionine betasynthase. MTHFR requires folate and vitamin B12 as cofactors, while cystathionine beta- synthase requires vitamin B6 [5]. Homocysteine plasma levels vary widely in the general popu- lation and can be affected by a number of factors, including folate and vitamin B12 [6]. Plasma hcy can also be influenced by the poly- morphism of the MTHFR gene characterized by a base substitution from C to T on residue 677. T677 allele occurs in 35% of caucasian populations, with up to 10–20% TT homozygotes [7]. Carriers of the TT677 MTHFR genotype frequently exhibit elevated plasma hcy 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.02.028