THESIS AWARD Nutrition and brain aging: role of fatty acids with an epidemiological perspective Cecilia SAMIERI Abstract: In the absence of identified etiologic treatment for dementia, the potential Pascale BARBERGER-GATEAU preventive role of nutrition may offer an interesting perspective. The objective of the thesis of C. Samieri was to study the association between nutrition and brain aging in Inserm, U897, 1,796 subjects, aged 65 y or older, from the Bordeaux sample of the Three-City study, Equipe Epidemiologie de la nutrition with a particular emphasis on fatty acids. Considering the multidimensional nature of et des comportements alimentaires, nutritional data, several complementary strategies were used. At the global diet level, Universite Bordeaux Segalen, dietary patterns actually observed in the population were identified by exploratory Case 11, methods. Older subjects with a ‘‘healthy’’ pattern, who consumed more than 3.5 weekly 146 rue Leo-Saignat, servings of fish in men and more than 6 daily servings of fruits and vegetables in women, F-33076 Bordeaux cedex, showed a better cognitive and psychological health. Adherence to the Mediterranean France diet, measured according to a score-based confirmatory method, was associated with <[email protected]. slower global cognitive decline after 5 y of follow-up. At the nutrient biomarker level, fr> higher plasma eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid, was associated with a decreased dementia risk, and the omega-6-to-omega-3 fatty acids ratio to an increased risk, particularly in depressed subjects. EPA was also related to slower working memory decline in depressed subjects or in carriers of the e4 allele of the ApoE gene. Docosahexaenoic acid was related to slower working memory decline only in ApoE4 carriers. Overall, this work suggests a positive impact of a healthy diet rich in fruits and vegetables and fish, and notably the Mediterranean diet, on cognition in older subjects. Long-chain n-3 PUFA, in particular EPA, may be key protective nutrients against risk of dementia and cognitive decline. Key words: diet, nutrition, cognition, aging, fatty acids, omega-3 With the aging of populations, demen- diagnosed when the onset of cognitive 2010). Indeed, while dementia diag- tia and Alzheimer’s disease (AD) as its impairment is progressive and insidious nosis is made when cognitive impair- more frequent form, has become an and when no other systemic or brain ment is widespread enough to important concern worldwide (Brayne, disease may account for the progres- generate disability, the first cognitive 2007). In the absence of promising sive cognitive deficits. AD specific symptoms start more than 10 y before treatment, the prevalence of late-life brain lesions include extracellular accu- (Amieva et al., 2008), and the first dementia is expected to double every mulation of b-amyloid peptides and brain lesions leading to neurodegen- 20 y, reaching 115 millions by 2050 intracellular accumulation of hyper- eration could occur decades before the (Prince and Jackson, 2009). Therefore, phosphorylated protein Tau. New clinical manifestations (Reiman et al., finding strategies capable of reducing research criteria have been recently 2004). This long time-lag between the the burden of AD is a major societal and proposed, combining evidence of AD first lesions in the brain and the clinical public health challenge. pathology based on neuroimaging and symptoms defines a large window of There is no definite diagnostic test for biological biomarkers, and clinical signs opportunity for potential preventive dementia and AD. The diagnosis of of memory impairment of the hippo- factors, before irreversible neurode- dementia is based on clinical evidence campal type (episodic memory) (Dubois generation. of both a memory disorder and impair- et al., 2007). An important feature for the study of risk ment in at least one other cognitive AD has been recently defined as a factors of brain aging is that late-life domain, both of which interfere with complex clinico-biological entity, char- dementia is multifactorial. It results from doi: 10.1684/ocl.2011.0397 activities of daily living (American acterized by a long-term pathological AD specific lesions and other lesions also Psychiatric Association, 2000). AD is process (Dubois et al., 2010; Jack et al., found in normal aging such as vascular To cite this article: Samieri C, Barberger-Gateau P. Nutrition and brain aging: role of fatty acids with an epidemiological perspective. OCL 2011; 18(4): 228-35. doi : 10.1684/ocl.2011.0397 228 OCL VOL. 18 N8 4 juillet-aouˆ t 2011 Article disponible sur le site http://www.ocl-journal.org ou http://dx.doi.org/10.1051/ocl.2011.0397 lesions, inflammation and oxidative In addition, other foods and nutrients, association between plasma fatty acids stress, both balanced by compensatory such as fruits and vegetables rich in and future dementia risk and cognitive mechanisms. Accordingly, a life-course antioxidant compounds and folates, decline, taking into account the potential etiologic model of dementia has been were evoked as potential preventive modifying role of depressive symptoms proposed, in which genetic risk factors factors in brain aging (Feart et al., and the ApoE4 allele. may interact with environmental factors 2010). More generally, nutrients and to modulate the risk of dementia and AD foods are consumed in combination, so The Three-City cohort (Fotuhi et al., 2009). Age is the strongest they could exert additive or synergistic known risk factor for AD, followed by effects on brain aging, which may not study genetic susceptibility, conferred by the be captured in single-nutrient based e e Cohort studies offer a unique opportu- 4 allele of the ApoE (ApoE 4) gene, studies (Moeller et al., 2007). Dietary nity to assess risk factors of dementia and which increases the risk of AD by 3 times patterns, which represent a combina- AD early in the course of the disease, in Causasian heterozygotes and by 15 tion of foods, may be better associated before the clinical phase associated times in homozygotes (Farrer et al., to disease risk than single foods or with widespread and irreversible brain 1997). Moreover, novel susceptibility nutrients. damage. These analyses were conducted genes for AD have been recently Dietary patterns have been classified into within the Bordeaux sample of the identified (Sleegers et al., 2010). Among two main categories (Moeller et al., 3C study, a prospective cohort study of environmental risk factors, vascular risk 2007). Aprioridietary patterns are de- vascular risk factors for dementia which factors such as hypertension, diabetes, fined by scores, computed according to started in 1999-2000 and included high blood cholesterol or obesity at previous hypotheses on the beneficial or 9,294 community dwellers in Bordeaux midlife, have been associated with deleterious effects of nutritional factors (n = 2,104), Dijon (n = 4,931) and Mont- higher risk of dementia or higher cog- on health. A priori dietary patterns are pellier (n = 2,259), France (Three-City nitive decline, leading to progressive therefore classified under the category of Study Group, 2003). Baseline data col- evidence that cardiovascular diseases confirmatory methods. In contrast, a lection included socio-demographic and and dementia shared numerous com- posteriori dietary patterns are defined lifestyle characteristics, symptoms mon risk factors (Reitz et al., 2011). either by scores derived from principal and complaints, main chronic condi- Nutritional factors, capable of modulat- component analysis, or by specific clus- tions, neuropsychological testing, phys- ing vascular risk factors and probably ters derived from cluster analysis, both ical examination and blood sampling, having a direct impact on brain func- strategies being undertaken without any enabling to perform ApoE genotyping. tion, have emerged as interesting can- prior hypothesis on the diet-disease Four follow-up examinations were per- didates for prevention, especially long- relationship. Thus, a posteriori dietary formed 2, 4, 7 and 10 y after baseline. chain omega-3 polyunsaturated fatty patterns fit to the definition of explora- acids (n-3 PUFA). At each visit, cognitive performance was tory methods. assessed by trained psychologists using Indeed, long-chain n-3 PUFA may exert Considering the multidimensional a battery of neuropsychological tests, beneficial effects against brain aging, nature of nutritional data, an accurate including: the Mini Mental State Exami- explained by their major structural and study of the relationship between nutri- nation (MMSE), assessing global cogni- functional role in neurone membranes, tion and brain aging must therefore tive function; the Isaac’s Set test (IST), vascular and anti-inflammatory proper- include two complementary approaches assessing verbal fluency; the Benton ties as well as their potential ability to to estimate nutritional exposure: a Visual Retention Test (BVRT), assessing modulate neuro-inflammation and the whole-diet approach (e.g global level) working memory; Trails Making tests expression of neuronal-plasticity related and a nutrient-based approach. The part A (TMT-A) and B (TMT-B), assessing genes (see for review (Cunnane et al., main objective of the thesis of C. Samieri executive functioning; and the Free and 2009)). Several longitudinal epidemio- summarized in this report was to study, Cued Selective Reminding Test (FCSRT), logical studies suggested a protective with an epidemiological perspective (e.g. assessing episodic memory. Diagnosis association between fish consumption, at the population level), the relationship of dementia was based on a three-step the main source of long-chain n-3 PUFA between nutrition and brain aging in procedure. All potential prevalent and in humans, or eicosapentaenoic acid 1,796 subjects, aged 65 y or older, from incident cases of dementia were inves- (EPA) and docosahexaenoic acid (DHA) the Bordeaux sample of the three-City tigated and reviewed by an indepen- consumption and cognitive decline or (3C) study. A particular interest was dent committee of neurologists to dementia risk. However, fewer studies given to n-3 PUFA.