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Martin M, Boulaire M, Lucas C, Peltier A, Pourtau L, Gaudout D, Layé S, Pallet V, Joffre C, Dinel AL. Plant Extracts and ω-3 Improve Short-Term Memory and Modulate the Microbiota-Gut-Brain Axis in D-galactose Model Mice. J Nutr 2024; 154:3704-3717. [PMID: 39332773 DOI: 10.1016/j.tjnut.2024.09.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND Aging, characterized by a slow and progressive alteration of cognitive functions, is associated with gut microbiota dysbiosis, low-grade chronic inflammation, as well as increased oxidative stress and neurofunctional alterations. Some nutrients, such as polyphenols, carotenoids, and omega (ω)-3 (n-3), are good candidates to prevent age-related cognitive decline, because of their immunomodulatory, antioxidant, and neuroprotective properties. OBJECTIVES The objective of this study was to demonstrate the preventive effect of a combination of plant extracts (PE) containing Memophenol™ (grapes and blueberries polyphenols) and a patented saffron extract (saffron carotenoids and safranal) and ω-3 on cognitive function in a mouse model of accelerated aging and to understand the biological mechanisms involved. METHODS We used an accelerated-aging model by injecting 3-mo-old male C57Bl6/J mice with D-galactose for 8 wk, during which they were fed with a balanced control diet and supplemented or not with PE and/or ω-3 (n = 15-16/group). Short-term memory was evaluated by Y-maze test, following analyses of hippocampal and intestinal RNA expressions, brain fatty acid and oxylipin amounts, and gut microbiota composition (16S rRNA gene sequencing). Statistical analyses were performed (t test, analysis of variance, and Pearson correlation). RESULTS Our results showed that oral administration of PE, ω-3, or both (mix) prevented hippocampus-dependent short-term memory deficits induced by D-galactose (P < 0.05). This effect was accompanied by the modulation of gut microbiota, altered by the treatment. PE and the mix increased the expression of antioxidative and neurogenesis markers, such as catalase and doublecortin, in hippocampus (P < 0.05 for both). Moreover, ω-3 and the mix showed a higher ω-3 amounts (P < 0.05) and EPA-derived 18- hydroxyeicosapentaenoic acid (P < 0.001) in prefrontal cortex. These changes may contribute to the improvement in memory. CONCLUSIONS These results suggest that the mix of PE and ω-3 could be more efficient at attenuating age-related cognitive decline than individual supplementations because it targeted, in mice, the different pathways impaired with aging.
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Affiliation(s)
- Marie Martin
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France; Activ'Inside, 12 route de Beroy, ZA du Grand Cazeau, Beychac-et-Caillau
| | - Milan Boulaire
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France
| | - Céline Lucas
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France; NutriBrain Research and Technology Transfer, NutriNeuro, Bordeaux, France
| | - Adrien Peltier
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France; NutriBrain Research and Technology Transfer, NutriNeuro, Bordeaux, France
| | - Line Pourtau
- Activ'Inside, 12 route de Beroy, ZA du Grand Cazeau, Beychac-et-Caillau
| | - David Gaudout
- Activ'Inside, 12 route de Beroy, ZA du Grand Cazeau, Beychac-et-Caillau
| | - Sophie Layé
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France
| | - Véronique Pallet
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France
| | - Corinne Joffre
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France
| | - Anne-Laure Dinel
- Université Bordeaux, INRAE, Bordeaux INP, Nutrineuro, Bordeaux, France; NutriBrain Research and Technology Transfer, NutriNeuro, Bordeaux, France.
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Arciniega H, Baucom ZH, Tuz-Zahra F, Tripodis Y, John O, Carrington H, Kim N, Knyazhanskaya EE, Jung LB, Breedlove K, Wiegand TLT, Daneshvar DH, Rushmore RJ, Billah T, Pasternak O, Coleman MJ, Adler CH, Bernick C, Balcer LJ, Alosco ML, Koerte IK, Lin AP, Cummings JL, Reiman EM, Stern RA, Shenton ME, Bouix S. Brain morphometry in former American football players: findings from the DIAGNOSE CTE research project. Brain 2024; 147:3596-3610. [PMID: 38533783 PMCID: PMC11449133 DOI: 10.1093/brain/awae098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 02/16/2024] [Accepted: 03/02/2024] [Indexed: 03/28/2024] Open
Abstract
Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.
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Affiliation(s)
- Hector Arciniega
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- Department of Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
- NYU Concussion Center, NYU Langone Health, New York, NY 10016, USA
| | - Zachary H Baucom
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Fatima Tuz-Zahra
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Yorghos Tripodis
- Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
| | - Omar John
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- Department of Rehabilitation Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
- NYU Concussion Center, NYU Langone Health, New York, NY 10016, USA
| | - Holly Carrington
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
| | - Nicholas Kim
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
| | - Evdokiya E Knyazhanskaya
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
| | - Leonard B Jung
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- cBRAIN, Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy, University Hospital Ludwig-Maximilians-Universität, Munich, Bavaria 80336, Germany
| | - Katherine Breedlove
- Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Tim L T Wiegand
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- cBRAIN, Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy, University Hospital Ludwig-Maximilians-Universität, Munich, Bavaria 80336, Germany
| | - Daniel H Daneshvar
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA 02115, USA
- Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA 02129, USA
| | - R Jarrett Rushmore
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
| | - Tashrif Billah
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
| | - Ofer Pasternak
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Michael J Coleman
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
| | - Charles H Adler
- Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
| | - Charles Bernick
- Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, USA
- Department of Neurology, University of Washington, Seattle, WA 98195, USA
| | - Laura J Balcer
- Department of Neurology, NYU Grossman School of Medicine, New York, NY 10017, USA
- Department of Population Health, NYU Grossman School of Medicine, New York, NY 10017, USA
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10017, USA
| | - Michael L Alosco
- Department of Neurology, Boston University Alzheimer’s Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
| | - Inga K Koerte
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- cBRAIN, Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy, University Hospital Ludwig-Maximilians-Universität, Munich, Bavaria 80336, Germany
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
- Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität, 82152 Munich, Bavaria, Germany
| | - Alexander P Lin
- Center for Clinical Spectroscopy, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jeffrey L Cummings
- Chambers-Grundy Center for Transformative Neuroscience, Pam Quirk Brain Health and Biomarker Laboratory, Department of Brain Health School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
| | - Eric M Reiman
- Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium, Phoenix, AZ 85006, USA
- Department of Psychiatry, University of Arizona, Phoenix, AZ 85004, USA
- Department of Psychiatry, Arizona State University, Phoenix, AZ 85008, USA
- Neurogenomics Division, Translational Genomics Research Institute and Alzheimer’s Consortium, Phoenix, AZ 85004, USA
| | - Robert A Stern
- Department of Anatomy and Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
- Department of Neurology, Boston University Alzheimer’s Disease Research Center and CTE Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
- Department of Neurosurgery, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA
| | - Martha E Shenton
- Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02145, USA
- Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Sylvain Bouix
- Department of Software Engineering and Information Technology, École de technologie supérieure, Université du Québec, Montréal, QC H3C 1K3, Canada
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Belaidi AA, Masaldan S, Southon A, Kalinowski P, Acevedo K, Appukuttan AT, Portbury S, Lei P, Agarwal P, Leurgans SE, Schneider J, Conrad M, Bush AI, Ayton S. Apolipoprotein E potently inhibits ferroptosis by blocking ferritinophagy. Mol Psychiatry 2024; 29:211-220. [PMID: 35484240 PMCID: PMC9757994 DOI: 10.1038/s41380-022-01568-w] [Citation(s) in RCA: 47] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 03/27/2022] [Accepted: 04/06/2022] [Indexed: 02/08/2023]
Abstract
Allelic variation to the APOE gene confers the greatest genetic risk for sporadic Alzheimer's disease (AD). Independent of genotype, low abundance of apolipoprotein E (apoE), is characteristic of AD CSF, and predicts cognitive decline. The mechanisms underlying the genotype and apoE level risks are uncertain. Recent fluid and imaging biomarker studies have revealed an unexpected link between apoE and brain iron, which also forecasts disease progression, possibly through ferroptosis, an iron-dependent regulated cell death pathway. Here, we report that apoE is a potent inhibitor of ferroptosis (EC50 ≈ 10 nM; N27 neurons). We demonstrate that apoE signals to activate the PI3K/AKT pathway that then inhibits the autophagic degradation of ferritin (ferritinophagy), thus averting iron-dependent lipid peroxidation. Using postmortem inferior temporal brain cortex tissue from deceased subjects from the Rush Memory and Aging Project (MAP) (N = 608), we found that the association of iron with pathologically confirmed clinical Alzheimer's disease was stronger among those with the adverse APOE-ε4 allele. While protection against ferroptosis did not differ between apoE isoforms in vitro, other features of ε4 carriers, such as low abundance of apoE protein and higher levels of polyunsaturated fatty acids (which fuel ferroptosis) could mediate the ε4 allele's heighted risk of AD. These data support ferroptosis as a putative pathway to explain the major genetic risk associated with late onset AD.
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Affiliation(s)
- Abdel Ali Belaidi
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Shashank Masaldan
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Adam Southon
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Pawel Kalinowski
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Karla Acevedo
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Ambili T Appukuttan
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Stuart Portbury
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia
| | - Peng Lei
- Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Puja Agarwal
- Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, United States
| | - Sue E Leurgans
- Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, United States
| | - Julie Schneider
- Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, United States
| | - Marcus Conrad
- Helmholtz Zentrum München, Institute of Metabolism and Cell Death, 85764, Neuherberg, Germany
- Pirogov Russian National Research Medical University, Laboratory of Experimental Oncology, Moscow, 117997, Russia
| | - Ashley I Bush
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia.
| | - Scott Ayton
- Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia.
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González LM, Bourissai A, Lessard-Beaudoin M, Lebel R, Tremblay L, Lepage M, Graham RK. Amelioration of Cognitive and Olfactory System Deficits in APOE4 Transgenic Mice with DHA Treatment. Mol Neurobiol 2023; 60:5624-5641. [PMID: 37329383 DOI: 10.1007/s12035-023-03401-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/24/2023] [Indexed: 06/19/2023]
Abstract
Olfactory dysfunction and atrophy of olfactory brain regions are observed early in mild cognitive impairment and Alzheimer disease. Despite substantial evidence showing neuroprotective effects in MCI/AD with treatment of docosahexaenoic acid (DHA), an omega-3 fatty acid, few studies have assessed DHA and its effects on the olfactory system deficits. We therefore performed structural (MRI), functional (olfactory behavior, novel object recognition), and molecular (markers of apoptosis and inflammation) assessments of APOE4 and wild-type mice ± DHA treatment at 3, 6, and 12 months of age. Our results demonstrate that APOE4 mice treated with the control diet show recognition memory deficits, abnormal olfactory habituation, and discrimination abilities and an increase in IBA-1 immunoreactivity in the olfactory bulb. These phenotypes were not present in APOE4 mice treated with a DHA diet. Alterations in some brain regions' weights and/or volumes were observed in the APOPE4 mice and may be due to caspase activation and/or neuroinflammatory events. These results suggest that the consumption of a diet rich in DHA may provide some benefit to E4 carriers but may not alleviate all symptoms.
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Affiliation(s)
- Laura Martínez González
- Research Centre on Aging CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Avenue Nord, QC, J1H 5N4, Sherbrooke, Canada
| | - Adam Bourissai
- Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Mélissa Lessard-Beaudoin
- Research Centre on Aging CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Avenue Nord, QC, J1H 5N4, Sherbrooke, Canada
| | - Réjean Lebel
- Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Luc Tremblay
- Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Martin Lepage
- Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Faculty of Medicine and Health Sciences, Sherbrooke, Quebec, J1H 5N4, Canada
| | - Rona K Graham
- Research Centre on Aging CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada.
- Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12e Avenue Nord, QC, J1H 5N4, Sherbrooke, Canada.
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Rouch L, Virecoulon Giudici K, Cantet C, Guyonnet S, Delrieu J, Legrand P, Catheline D, Andrieu S, Weiner M, de Souto Barreto P, Vellas B, for the Alzheimer's Disease Neuroimaging Initiative. Associations of erythrocyte omega-3 fatty acids with cognition, brain imaging and biomarkers in the Alzheimer's disease neuroimaging initiative: cross-sectional and longitudinal retrospective analyses. Am J Clin Nutr 2022; 116:1492-1506. [PMID: 36253968 PMCID: PMC9761759 DOI: 10.1093/ajcn/nqac236] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 08/30/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The association between omega-3 (ω-3) PUFAs and cognition, brain imaging and biomarkers is still not fully established. OBJECTIVES The aim was to analyze the cross-sectional and retrospective longitudinal associations between erythrocyte ω-3 index and cognition, brain imaging, and biomarkers among older adults. METHODS A total of 832 Alzheimer's Disease Neuroimaging Initiative 3 (ADNI-3) participants, with a mean (SD) age of 74.0 (7.9) y, 50.8% female, 55.9% cognitively normal, 32.7% with mild cognitive impairment, and 11.4% with Alzheimer disease (AD) were included. A low ω-3 index (%EPA + %DHA) was defined as the lowest quartile (≤3.70%). Cognitive tests [composite score, AD Assessment Scale Cognitive (ADAS-Cog), Wechsler Memory Scale (WMS), Trail Making Test, Category Fluency, Mini-Mental State Examination, Montreal Cognitive Assessment] and brain variables [hippocampal volume, white matter hyperintensities (WMHs), positron emission tomography (PET) amyloid-β (Aβ) and tau] were considered as outcomes in regression models. RESULTS Low ω-3 index was not associated with cognition, hippocampal, and WMH volume or brain Aβ and tau after adjustment for demographics, ApoEε4, cardiovascular disease, BMI, and total intracranial volume in the cross-sectional analysis. In the retrospective analysis, low ω-3 index was associated with greater Aβ accumulation (adjusted β = 0.02; 95% CI: 0.01, 0.03; P = 0.003). The composite cognitive score did not differ between groups; however, low ω-3 index was significantly associated with greater WMS-delayed recall cognitive decline (adjusted β = -1.18; 95% CI: -2.16, -0.19; P = 0.019), but unexpectedly lower total ADAS-Cog cognitive decline. Low ω-3 index was cross-sectionally associated with lower WMS performance (adjusted β = -1.81, SE = 0.73, P = 0.014) and higher tau accumulation among ApoE ε4 carriers. CONCLUSIONS Longitudinally, low ω-3 index was associated with greater Aβ accumulation and WMS cognitive decline but unexpectedly with lower total ADAS-Cog cognitive decline. Although no associations were cross-sectionally found in the whole population, low ω-3 index was associated with lower WMS cognition and higher tau accumulation among ApoE ε4 carriers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is registered at clinicaltrials.gov as NCT00106899.
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Affiliation(s)
- Laure Rouch
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
| | | | - Christelle Cantet
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
| | - Sophie Guyonnet
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
- CERPOP Centre d'Epidémiologie et de Recherche en Santé des Populations, Institut National de la Santé et de la Recherche Médicale 1295, University of Toulouse, Toulouse, France
| | - Julien Delrieu
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
- CERPOP Centre d'Epidémiologie et de Recherche en Santé des Populations, Institut National de la Santé et de la Recherche Médicale 1295, University of Toulouse, Toulouse, France
- Toulouse NeuroImaging Center, Université de Toulouse, Institut National de la Santé et de la Recherche Médicale, UPS, Toulouse, France
| | - Philippe Legrand
- Laboratory of Biochemistry and Human Nutrition, Institut Agro, Institut National de la Santé et de la Recherche Médicale 1241, Rennes, France
| | - Daniel Catheline
- Laboratory of Biochemistry and Human Nutrition, Institut Agro, Institut National de la Santé et de la Recherche Médicale 1241, Rennes, France
| | - Sandrine Andrieu
- CERPOP Centre d'Epidémiologie et de Recherche en Santé des Populations, Institut National de la Santé et de la Recherche Médicale 1295, University of Toulouse, Toulouse, France
- Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France
| | - Michael Weiner
- Department of Veterans Affairs Medical Center, San Francisco, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA
| | - Philipe de Souto Barreto
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
- CERPOP Centre d'Epidémiologie et de Recherche en Santé des Populations, Institut National de la Santé et de la Recherche Médicale 1295, University of Toulouse, Toulouse, France
| | - Bruno Vellas
- Gerontopole of Toulouse, Institute of Ageing, Toulouse University Hospital, Toulouse, Franc
- CERPOP Centre d'Epidémiologie et de Recherche en Santé des Populations, Institut National de la Santé et de la Recherche Médicale 1295, University of Toulouse, Toulouse, France
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6
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Zhou L, Xiong JY, Chai YQ, Huang L, Tang ZY, Zhang XF, Liu B, Zhang JT. Possible antidepressant mechanisms of omega-3 polyunsaturated fatty acids acting on the central nervous system. Front Psychiatry 2022; 13:933704. [PMID: 36117650 PMCID: PMC9473681 DOI: 10.3389/fpsyt.2022.933704] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) can play important roles in maintaining mental health and resistance to stress, and omega-3 PUFAs supplementation can display beneficial effects on both the prevention and treatment of depressive disorders. Although the underlying mechanisms are still unclear, accumulated evidence indicates that omega-3 PUFAs can exhibit pleiotropic effects on the neural structure and function. Thus, they play fundamental roles in brain activities involved in the mood regulation. Since depressive symptoms have been assumed to be of central origin, this review aims to summarize the recently published studies to identify the potential neurobiological mechanisms underlying the anti-depressant effects of omega-3 PUFAs. These include that of (1) anti-neuroinflammatory; (2) hypothalamus-pituitary-adrenal (HPA) axis; (3) anti-oxidative stress; (4) anti-neurodegeneration; (5) neuroplasticity and synaptic plasticity; and (6) modulation of neurotransmitter systems. Despite many lines of evidence have hinted that these mechanisms may co-exist and work in concert to produce anti-depressive effects, the potentially multiple sites of action of omega-3 PUFAs need to be fully established. We also discussed the limitations of current studies and suggest future directions for preclinical and translational research in this field.
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Affiliation(s)
- Lie Zhou
- Yangtze University Health Science Center, Jingzhou, China
- Mental Health Institute of Yangtze University, Jingzhou, China
| | - Jia-Yao Xiong
- Yangtze University Health Science Center, Jingzhou, China
| | - Yu-Qian Chai
- Yangtze University Health Science Center, Jingzhou, China
| | - Lu Huang
- Yangtze University Health Science Center, Jingzhou, China
- Mental Health Institute of Yangtze University, Jingzhou, China
| | - Zi-Yang Tang
- Yangtze University Health Science Center, Jingzhou, China
- Mental Health Institute of Yangtze University, Jingzhou, China
- Jingzhou Mental Health Center, Jingzhou, China
| | - Xin-Feng Zhang
- Mental Health Institute of Yangtze University, Jingzhou, China
- Jingzhou Mental Health Center, Jingzhou, China
| | - Bo Liu
- Mental Health Institute of Yangtze University, Jingzhou, China
- Jingzhou Mental Health Center, Jingzhou, China
| | - Jun-Tao Zhang
- Yangtze University Health Science Center, Jingzhou, China
- Mental Health Institute of Yangtze University, Jingzhou, China
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7
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Kozielec-Oracka BJ, Min Y, Bhullar AS, Stasiak B, Ghebremeskel K. Plasma and red blood cell n3 fatty acids correlate positively with the WISC-R verbal and full-scale intelligence quotients and inversely with Conner's parent-rated ADHD index t-scores in children with high functioning autism and Asperger's syndrome. Prostaglandins Leukot Essent Fatty Acids 2022; 178:102414. [PMID: 35338846 DOI: 10.1016/j.plefa.2022.102414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 11/25/2022]
Abstract
Findings of the fatty acid status of people with autism spectrum disorders have been incongruent perhaps because of the diversity of the condition. A cross-sectional design study was used to investigated fatty acid levels and relationships between fatty acids, and cognition and behaviour in a homogenous group of children with autism spectrum disorder. Children with Asperger's syndrome (AS) /high functioning autism (n = 44) and healthy siblings (n = 17) were recruited from the Diagnostic and Therapeutic Centre for Children with Autism, Warsaw, Poland. In the AS group, plasma phosphatidylcholine 22:5n3 correlated positively with verbal (r = 0.357, p = 0.019) and full scale (r = 0.402, p = 0.008) IQs, red blood cell phosphatidylcholine 22:5n3 with verbal (r = 0.308, p = 0.044), performance (r = 0.304, p = 0.047) and full scale (r = 0.388, p = 0.011) IQs and red blood cell phosphatidylethanolamine 22:5n3 with verbal (r = 0.390, p = 0.010) and full scale (r = 0.370, p = 0.016) IQs. Whilst, plasma phosphatidycholine 20:5n3 (r = -0.395, p = 0.009), 22:6n3 (r = -0.402, p = 0.007) and total n3 fatty acids (r = -425, p = 0.005), red blood cell phosphatidlycholine 20:5n3 (r = -0.321, p = 0.036) and red blood cell phosphatidylethanolamine 20:5n3 (r = -0.317, p = 0.038), 22:6n3 (r = -0.297, p = 0.05) and total n3 fatty acids (r = -0.306, p = 0.046) correlated inversly with ADHD index. Similarly, inattention was negatively related with plasma phosphatidylcholine 22:6n3 (r = -0.335, p = 0.028), and total n3 fatty acids (r = -0.340, p = 0.026), oppositional with plasma phosphatidylcholine 18:3n3 (r = -0.333, p = 0.029), 20:5n3 (r = -0.365, p = 0.016), total n3 fatty acids (r = -0.293, p < 0.05), red blood cell phosphatidylcholine 18:3n3 (r = -0.337, p = 0.027) and red blood cell ethanolamine 18:3n3 (r = - 0.333, p = 0.029), 20:5n3 (r = -0.328, p = 0.032), 22:6n3 (r = 0.362, p = 0.017) and total n-3 fatty acids (r = -0.298, p < 0.05) and hyperactivity with plasma phosphatidylcholine 22:6n3 (r = -0.320, p = 0.039). In contrast, there were inverse correlations between red blood cell phosphatidylcholine 18:2n6 and performance (r = -0.358, p = 0.019) and full scale (r = -0.320, p = 0.039) IQs, and direct correlations between red blood cell phosphatidylcholine 22:4n6 (r = 0.339, p = 0.026) and 22:5n6 (r = 0.298, p < 0.05) and ADHD index, between red blood cell phosphatidylcholine 22:4n6 (r = 0.308, p = 0.044) and inattention, between plasma phosphatidylcholine 22:4n6 (r = 0.341, p = 0.025), red blood cell phosphatidylcholine 20:4n6 (r = 0.314, p = 0.041) and total n6 fatty acids (r = 0.336, p = 0.028) and oppositional and plasma phosphatidylcholine 20:3n6 (r = 0.362, p = 0.018) and red blood cell phosphatidylcholine 20:3n6 (r = 0.401, p = 0.009) and hyperactivity. The findings of the ethnically homogenous children with Asperger's syndrome/high functioning autism study revealed positive associations between 22:5n3 and cognition, and negative relationships between 20:5n3 and 22:6n3 and behavioural problem. In contrast, cognitive ability and behavioural problems were negatively and positively associated with n6 fatty acids. Further investigation is required to establish whether there a cause and effect relationship. Regardless, it would be prudent to ensure that children with the conditions have optimum n3 PUFA intake.
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Affiliation(s)
| | - Yoeju Min
- Lipidomics and Nutrition Research Centre, School of Human Sciences, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK
| | - Amritpal S Bhullar
- Division of Human Nutrition, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
| | - Barbara Stasiak
- Mental Health Clinic for Children and Youth, Masovian Neuropsychiatry Center, Warsaw, Poland
| | - Kebreab Ghebremeskel
- Lipidomics and Nutrition Research Centre, School of Human Sciences, London Metropolitan University, 166-220 Holloway Road, London N7 8DB, UK.
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8
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Samieri C, Yassine HN, Melo van Lent D, Lefèvre-Arbogast S, van de Rest O, Bowman GL, Scarmeas N. Personalized nutrition for dementia prevention. Alzheimers Dement 2021; 18:1424-1437. [PMID: 34757699 DOI: 10.1002/alz.12486] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 08/26/2021] [Accepted: 08/30/2021] [Indexed: 12/17/2022]
Abstract
The role of nutrition has been investigated for decades under the assumption of one-size-fits-all. Yet there is heterogeneity in metabolic and neurobiological responses to diet. Thus a more personalized approach may better fit biological reality and have increased efficacy to prevent dementia. Personalized nutrition builds on the food exposome, defined as the history of diet-related exposures over the lifetime, and on its interactions with the genome and other biological characteristics (eg, metabolism, the microbiome) to shape health. We review current advances of personalized nutrition in dementia research. We discuss key questions, success milestones, and future roadmap from observational epidemiology to clinical studies through basic science. A personalized nutrition approach based on the best prescription for the most appropriate target population in the most relevant time-window has the potential to strengthen dementia-prevention efforts.
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Affiliation(s)
- Cécilia Samieri
- Univ. Bordeaux, ISPED, Inserm, Bordeaux Population Health Research Center, Bordeaux, France
| | - Hussein N Yassine
- Department of Medicine, Keck School of Medicine USC, Los Angeles, California, USA.,Department of Neurology, Keck School of Medicine USC, Los Angeles, California, USA
| | - Debora Melo van Lent
- Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, Texas, USA.,Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
| | | | - Ondine van de Rest
- Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, the Netherlands
| | - Gene L Bowman
- Department of Neurology and Layton Aging and Alzheimer's Disease Center, Oregon Health and Science University, Portland, Oregon, USA.,Helfgott Research Institute, National University of Natural Medicine, Portland, Oregon, USA
| | - Nikolaos Scarmeas
- 1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece.,Taub Institute for Research in Alzheimer's Disease and the Aging Brain, The Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, New York, USA
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9
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Jin X, Xiong S, Yuan C, Gong E, Zhang X, Yao Y, Leng Y, Niu Z, Zeng Y, Yan LL. Apolipoprotein E Genotype, Meat, Fish, and Egg Intake in Relation to Mortality Among Older Adults: A Longitudinal Analysis in China. Front Med (Lausanne) 2021; 8:697389. [PMID: 34355006 PMCID: PMC8329349 DOI: 10.3389/fmed.2021.697389] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 06/22/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: The interactions between apolipoprotein E (APOE) genotype and diet pattern changes were found significant in several trials, implying that APOE gene may modify the effect of animal protein-rich food on health outcomes. We aim to study the interaction of APOE genotype with the effect of meat, fish and egg intake on mortality. Methods: This population-based study enrolled 8,506 older adults (mean age: 81.7 years, 52.3% female) from the Chinese Longitudinal Healthy Longevity Study. The intake frequency of meat, fish and egg was assessed by 3-point questions at baseline. Cox regression was conducted to calculate the hazard ratios for all-cause mortality of intake levels of meat, fish and egg. The analyses were stratified by APOE genotype and sex. The analyses were performed in 2020. Results: In the multivariable-adjusted models, meat and fish intake was associated with all-cause mortality (high vs. low intake: meat: HR: 1.14, 95% CI: 1.01, 1.28; fish: HR: 0.83, 95% CI: 0.73, 0.95). APOE genotype have significant interactions with meat and fish intake (Ps < 0.05). Compared with low fish intake, high fish intake was associated with lower risk of mortality (HR: 0.74, 95% CI: 0.56–0.98) only among the APOE ε4 carriers. High meat intake was significantly associated with higher risks of mortality (HR: 1.13, 95% CI: 1.04–1.25) only among the APOE ε4 non-carriers. The interactive relationship was restricted among the male. No significant findings were observed between egg and mortality among carriers or non-carriers. Conclusions: Among Chinese older adults, the significance of associations of mortality with reported meat or fish intake depended on APOE-E4 carriage status. If validated by other studies, our findings provide evidence for gene-based “precision” lifestyle recommendations.
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Affiliation(s)
- Xurui Jin
- Global Health Research Center, Duke Kunshan University, Kunshan, China.,Mindrank AI Ltd, Hangzhou, China
| | - Shangzhi Xiong
- Global Health Research Center, Duke Kunshan University, Kunshan, China.,The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
| | - Changzheng Yuan
- Department of Big Data and Health Science, School of Public Health, School of Medicine, Zhejiang University, Hangzhou, China
| | - Enying Gong
- School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
| | | | - Yao Yao
- Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China
| | - Yu Leng
- Global Health Research Center, Duke Kunshan University, Kunshan, China
| | | | - Yi Zeng
- Center for Healthy Aging and Development Studies, National School of Development, Peking University, Beijing, China.,Center for the Study of Aging and Human Development and Geriatrics Division, Medical School of Duke University, Durham, NC, United States.,Duke Global Health Institute, Duke University, Durham, NC, United States
| | - Lijing L Yan
- Global Health Research Center, Duke Kunshan University, Kunshan, China.,Duke Global Health Institute, Duke University, Durham, NC, United States.,The George Institute for Global Health, Beijing, China.,Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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10
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Cutuli D, Landolfo E, Nobili A, De Bartolo P, Sacchetti S, Chirico D, Marini F, Pieroni L, Ronci M, D'Amelio M, D'Amato FR, Farioli-Vecchioli S, Petrosini L. Behavioral, neuromorphological, and neurobiochemical effects induced by omega-3 fatty acids following basal forebrain cholinergic depletion in aged mice. ALZHEIMERS RESEARCH & THERAPY 2020; 12:150. [PMID: 33198763 PMCID: PMC7667851 DOI: 10.1186/s13195-020-00705-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/12/2020] [Indexed: 12/13/2022]
Abstract
Background In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer’s disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology. Methods Aged mice first underwent mu-p75-saporin immunotoxin intraventricular lesions to obtain a massive cholinergic depletion and then were orally supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks. Four weeks after the beginning of the dietary supplementation, anxiety levels as well as mnesic, social, and depressive-like behaviors were evaluated. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were carried out. Results The n-3 PUFA treatment regulated the anxiety alterations and reverted the novelty recognition memory impairment induced by the cholinergic depletion in aged mice. Moreover, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA were positively related to mnesic abilities. Conclusions The demonstration that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD.
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Affiliation(s)
- Debora Cutuli
- IRCCS Fondazione Santa Lucia, Rome, Italy. .,University of Rome "Sapienza", Rome, Italy.
| | - Eugenia Landolfo
- IRCCS Fondazione Santa Lucia, Rome, Italy.,University of Rome "Sapienza", Rome, Italy
| | - Annalisa Nobili
- IRCCS Fondazione Santa Lucia, Rome, Italy.,University "Campus Bio-Medico", Rome, Italy
| | - Paola De Bartolo
- IRCCS Fondazione Santa Lucia, Rome, Italy.,Department of Human Sciences, Guglielmo Marconi University, Rome, Italy
| | | | - Doriana Chirico
- Institute of Biochemistry and Cell Biology, CNR, Monterotondo, Italy
| | - Federica Marini
- Università Cattolica del Sacro Cuore, Rome, Italy.,IRCCS Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | | | - Maurizio Ronci
- Department of Pharmacy, University G. D'Annunzio of Chieti-Pescara, Chieti, Italy
| | - Marcello D'Amelio
- IRCCS Fondazione Santa Lucia, Rome, Italy.,University "Campus Bio-Medico", Rome, Italy
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11
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Thomas A, Baillet M, Proust-Lima C, Féart C, Foubert-Samier A, Helmer C, Catheline G, Samieri C. Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk. Alzheimers Dement 2020; 17:407-416. [PMID: 33090665 DOI: 10.1002/alz.12195] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 11/09/2022]
Abstract
INTRODUCTION We searched for consistent associations of an omega-3 index in plasma (sum of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) with several dementia-related outcomes in a large cohort of older adults. METHODS We included 1279 participants from the Three-City study, non-demented at the time of blood measurements at baseline, with face-to-face neuropsychological assessment and systematic detection of incident dementia over a 17-year follow-up. An ancillary study included 467 participants with up to three repeated brain imaging exams over 10 years. RESULTS In multivariable models, higher levels of plasma EPA+DHA were consistently associated with a lower risk of dementia (hazard ratio for 1 standard deviation = 0.87 [95% confidence interval, 0.76-0.98]), and a lower decline in global cognition (P = .04 for change over time), memory (P = .06), and medial temporal lobe volume (P = .02). DISCUSSION This prospective study provides compelling evidence for a relationship between long-chain omega-3 fatty acids levels and lower risks for dementia and related outcomes.
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Affiliation(s)
- Aline Thomas
- INSERM, BPH, U1219, Univ. Bordeaux, Bordeaux, F-33000, France
| | - Marion Baillet
- INSERM, BPH, U1219, Univ. Bordeaux, Bordeaux, F-33000, France
| | | | - Catherine Féart
- INSERM, BPH, U1219, Univ. Bordeaux, Bordeaux, F-33000, France
| | - Alexandra Foubert-Samier
- INSERM, BPH, U1219, Univ. Bordeaux, Bordeaux, F-33000, France
- Institut des Maladies Neurodégénératives, Bordeaux Univ. Hospital, Bordeaux, F-33000, France
| | | | - Gwénaëlle Catheline
- CNRS, INCIA, UMR5287, Univ. Bordeaux, Bordeaux, F-33000, France
- Laboratoire Neuroimagerie et vie quotidienne, EPHE-PSL, Bordeaux, F-33000, France
| | - Cécilia Samieri
- INSERM, BPH, U1219, Univ. Bordeaux, Bordeaux, F-33000, France
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12
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Omega-3 and its domain-specific effects on cognitive test performance in youths: A meta-analysis. Neurosci Biobehav Rev 2020; 112:420-436. [DOI: 10.1016/j.neubiorev.2020.02.016] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 02/03/2020] [Accepted: 02/12/2020] [Indexed: 12/20/2022]
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13
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Brzezińska A, Bourke J, Rivera-Hernández R, Tsolaki M, Woźniak J, Kaźmierski J. Depression in Dementia or Dementia in Depression? Systematic Review of Studies and Hypotheses. Curr Alzheimer Res 2020; 17:16-28. [DOI: 10.2174/1567205017666200217104114] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 01/09/2020] [Accepted: 01/18/2020] [Indexed: 01/21/2023]
Abstract
The majority of research works to date suggest that Major Depressive Disorder (MDD) is a
risk factor for dementia and may predispose to cognitive decline in both early and late onset variants.
The presence of depression may not, however, reflect the cause, rather, an effect: it may be a response to
cognitive impairment or alters the threshold at which cognitive impairment might manifest or be detected.
An alternative hypothesis is that depression may be part of a prodrome to Alzheimer’s Disease
(AD), suggesting a neurobiological association rather than one of psychological response alone. Genetic
polymorphisms may explain some of the variances in shared phenomenology between the diagnoses, the
instance, when the conditions arise comorbidly, the order in which they are detected that may depend on
individual cognitive and physical reserves, as well as the medical history and individual vulnerability.
This hypothesis is biologically sound but has not been systematically investigated to date. The current
review highlights how genetic variations are involved in the development of both AD and MDD, and the
risk conferred by these variations on the expression of these two disorders comorbidly is an important
consideration for future studies of pathoaetiological mechanisms and in the stratification of study samples
for randomised controlled trials.
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Affiliation(s)
- Agnieszka Brzezińska
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Julius Bourke
- Centre for Psychiatry, Wolfson Institute for Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London E14NS, United Kingdom
| | - Rayito Rivera-Hernández
- Department of Psychiatry, Psychology, Legal Medicine and History of Medicine, University of Salamanca, Salamanca, Spain
| | - Magda Tsolaki
- 3rd Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece, “George Papanicolaou” Hospital, Thessaloniki, Greece
| | - Joanna Woźniak
- Central Clinical Hospital of Medical University of Lodz, Lodz, Poland
| | - Jakub Kaźmierski
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
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14
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Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice. Int J Mol Sci 2020; 21:ijms21051741. [PMID: 32143275 PMCID: PMC7084583 DOI: 10.3390/ijms21051741] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/24/2020] [Accepted: 03/01/2020] [Indexed: 01/05/2023] Open
Abstract
As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.
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15
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Wade AT, Tregoweth E, Greaves D, Olds TS, Buckley JD, Keage HAD, Coates AM, Smith AE. Long-Chain Omega-3 Fatty Acid Intake Is Associated with Age but not Cognitive Performance in an Older Australian Sample. J Nutr Health Aging 2020; 24:857-864. [PMID: 33009536 DOI: 10.1007/s12603-020-1405-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFA) are essential nutrients and may be capable of delaying age-related cognitive decline. However, previous studies indicate that Australians are not meeting recommendations for LCn-3 PUFA intake. The current study therefore examined LCn-3 PUFA intake in an older Australia sample, as well as associations between LCn-3 PUFA intake and cognitive function. METHODS Cross-sectional data were collected from 90 adults aged 50 to 80 years. LCn-3 PUFA intake was assessed using a food frequency questionnaire and red blood cell fatty acid profiles were used to calculate the Omega-3 Index (RBC n-3 index). Cognitive function was measured using Addenbrooke's Cognitive Examination-III. RESULTS Positive associations were observed between age and RBC n-3 index (b=0.06, 95% CI: 0.01 - 0.10, P=0.01), and age and LCn-3 PUFA intake from fish oil capsules (b=17.5, 95% CI: 2.4 - 32.5 mg/day, P=0.02). When adjusting for LCn-3 PUFA from fish oil capsules, the association between age and RBC n-3 index was no longer significant. No associations were observed between LCn-3 PUFA intake and cognitive function. CONCLUSION LCn-3 PUFA and fish oil consumption increased with age in this sample of older Australians, particularly due to supplement intake. However, LCn-3 PUFA intake was not associated with cognitive function.
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Affiliation(s)
- A T Wade
- Ashleigh E. Smith, Alliance for Research in Exercise Nutrition and Activity, Allied Health and Human Performance, University of South Australia, GPO Box 2471, Adelaide, South Australia 5001. Tel: +618 8302 1735.
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16
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Simonetto M, Infante M, Sacco RL, Rundek T, Della-Morte D. A Novel Anti-Inflammatory Role of Omega-3 PUFAs in Prevention and Treatment of Atherosclerosis and Vascular Cognitive Impairment and Dementia. Nutrients 2019; 11:2279. [PMID: 31547601 PMCID: PMC6835717 DOI: 10.3390/nu11102279] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/11/2019] [Accepted: 09/19/2019] [Indexed: 12/13/2022] Open
Abstract
Atherosclerosis is an inflammatory chronic disease affecting arterial vessels and leading to vascular diseases, such as stroke and myocardial infarction. The relationship between atherosclerosis and risk of neurodegeneration has been established, in particular with vascular cognitive impairment and dementia (VCID). Systemic atherosclerosis increases the risk of VCID by inducing cerebral infarction, or through systemic or local inflammatory factors that underlie both atherosclerosis and cognition. Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are involved in inflammatory processes, but with opposite roles. Specifically, omega-3 PUFAs exert anti-inflammatory properties by competing with omega-6 PUFAs and displacing arachidonic acid in membrane phospholipids, decreasing the production of pro-inflammatory eicosanoids. Experimental studies and some clinical trials have demonstrated that omega-3 PUFA supplementation may reduce the risk of different phenotypes of atherosclerosis and cardiovascular disease. This review describes the link between atherosclerosis, VCID and inflammation, as well as how omega-3 PUFA supplementation may be useful to prevent and treat inflammatory-related diseases.
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Affiliation(s)
- Marialaura Simonetto
- Department of Neurology and The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Marco Infante
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
| | - Ralph L Sacco
- Department of Neurology and The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Tatjana Rundek
- Department of Neurology and The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - David Della-Morte
- Department of Neurology and The Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.
- San Raffaele Roma Open University, 00166 Rome, Italy.
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17
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Nutrient Patterns, Cognitive Function, and Decline in Older Persons: Results from the Three-City and NuAge Studies. Nutrients 2019; 11:nu11081808. [PMID: 31387312 PMCID: PMC6723709 DOI: 10.3390/nu11081808] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/05/2022] Open
Abstract
Dietary patterns, or the combination of foods and beverages intake, have been associated with better cognitive function in older persons. To date, no study has investigated the link between a posteriori nutrient patterns based on food intake, and cognitive decline in longitudinal analyses. The aim of this study was to evaluate the relationship between nutrient patterns and cognitive function and decline in two longitudinal cohorts of older persons from France and Canada. The study sample was composed of participants from the Three-City study (3C, France) and the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge, Quebec, Canada). Both studies estimated nutritional intakes at baseline, and carried out repeated measures of global cognitive function for 1,388 and 1,439 individuals, respectively. Nutrient patterns were determined using principal component analysis methodology in the two samples, and their relation with cognitive function and decline was estimated using linear mixed models. In 3C, a healthy nutrient pattern, characterized by higher intakes of plant-based foods, was associated with a higher global cognitive function at baseline, as opposed to a Western nutrient pattern, which was associated with lower cognitive performance. In NuAge, we also found a healthy nutrient pattern and a Western pattern, although no association was observed with either of these patterns in the Canadian cohort. No association between any of the nutrient patterns and cognitive decline was observed in either cohort. There is a need for longitudinal cohorts focusing on nutrient patterns with substantial follow-up, in order to evaluate more accurately associations between nutrition and cognition in older persons.
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Abstract
Numerous health benefits are attributed to the n-3 long-chain PUFA (n-3 LCPUFA); EPA and DHA. A systematic literature review was conducted to investigate factors, other than diet, that are associated with the n-3 LCPUFA levels. The inclusion criteria were papers written in English, carried out in adult non-pregnant humans, n-3 LCPUFA measured in blood or tissue, data from cross-sectional studies, or baseline data from intervention studies. The search revealed 5076 unique articles of which seventy were included in the qualitative synthesis. Three main groups of factors potentially associated with n-3 LCPUFA levels were identified: (1) unmodifiable factors (sex, genetics, age), (2) modifiable factors (body size, physical activity, alcohol, smoking) and (3) bioavailability factors (chemically bound form of supplements, krill oil v. fish oil, and conversion of plant-derived α-linolenic acid (ALA) to n-3 LCPUFA). Results showed that factors positively associated with n-3 LCPUFA levels were age, female sex (women younger than 50 years), wine consumption and the TAG form. Factors negatively associated with n-3 LCPUFA levels were genetics, BMI (if erythrocyte EPA and DHA levels are <5·6 %) and smoking. The evidence for girth, physical activity and krill oil v. fish oil associated with n-3 LCPUFA levels is inconclusive. There is also evidence that higher ALA consumption leads to increased levels of EPA but not DHA. In conclusion, sex, age, BMI, alcohol consumption, smoking and the form of n-3 LCPUFA are all factors that need to be taken into account in n-3 LCPUFA research.
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Häberling I, Berger G, Schmeck K, Held U, Walitza S. Omega-3 Fatty Acids as a Treatment for Pediatric Depression. A Phase III, 36 Weeks, Multi-Center, Double-Blind, Placebo-Controlled Randomized Superiority Study. Front Psychiatry 2019; 10:863. [PMID: 31827448 PMCID: PMC6892434 DOI: 10.3389/fpsyt.2019.00863] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 11/04/2019] [Indexed: 11/13/2022] Open
Abstract
Background: Depressive disorders in childhood and adolescence are a major health problem and often follow a chronic course with severe consequences in later life. Depressive disorders cause the highest burden of disease in this age group across all medical conditions. Treatment adherence is usually very poor, and the use of antidepressant drugs is heavily debated, as suicidal ideations may increase, in particular in the early phase of treatment. Omega-3 fatty acids rich in eicosapentaenoic acid have shown some promising results in over a dozen small scale randomized controlled trials (RCTs) in adult major depressive disorders, with only very few published RCTs in children and adolescents. High-quality phase III RCTs are missing. Methods and Design: The omega-3-pMDD trial is a carefully designed phase III RCT to assess the efficacy and safety of omega-3 fatty acids in the early course of pediatric major depressive disorder (MDD). The study is designed as a multi-center, double-blinded, placebo-controlled, randomized clinical trial enrolling 220 patients aged 8 to 17 years meeting DSM-IV criteria for major depressive disorder of at least moderate symptom severity. After a single-blinded placebo-lead-in phase (7 to 10 days) patients are randomly assigned to omega-3 fatty acids or placebo over 36 weeks. Primary outcomes are changes in depression severity, as well as remission and recovery rates. Secondary outcome measures include the omega-3 index and inflammatory parameters as predictors of response. Data analysis will be performed in the intention-to-treat sample using a (generalized) linear random intercept regression model. Through sampling of blood, hair, saliva, and urine, further putative biological markers for depression and omega-3 fatty response will be investigated. Discussion: This trial addresses if omega-3 fatty acids play a role in the pathogenesis of pediatric MDDs and have antidepressant properties, in particular in clinically depressed children and adolescents with a pre-existing omega-3 fatty acid deficiency, increased markers of oxidative stress, and/or markers of (low grade) inflammation. Ethics and Dissemination: The study was approved by the local ethics committees. The results will be published in peer-reviewed journals irrespective of specific outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03167307.
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Affiliation(s)
- Isabelle Häberling
- Research Department of Child and Adolescent Psychiatry, University Hospital of Psychiatry Zurich of the University of Zurich, Zurich, Switzerland
| | - Gregor Berger
- Research Department of Child and Adolescent Psychiatry, University Hospital of Psychiatry Zurich of the University of Zurich, Zurich, Switzerland
| | - Klaus Schmeck
- Research Department of Child and Adolescent Psychiatry, Psychiatric University Hospitals Basel, University of Basel, Basel, Switzerland
| | - Ulrike Held
- Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Susanne Walitza
- Research Department of Child and Adolescent Psychiatry, University Hospital of Psychiatry Zurich of the University of Zurich, Zurich, Switzerland
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Low Phytanic Acid-Concentrated DHA Prevents Cognitive Deficit and Regulates Alzheimer Disease Mediators in an ApoE -/- Mice Experimental Model. Nutrients 2018; 11:nu11010011. [PMID: 30577526 PMCID: PMC6356727 DOI: 10.3390/nu11010011] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 12/14/2018] [Accepted: 12/15/2018] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is the main cause of dementia and cognitive impairment. It has been associated with a significant diminution of omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) levels in the brain. Clinical trials with DHA as a treatment in neurological diseases have shown inconsistent results. Previously, we reported that the presence of phytanic acid (PhA) in standard DHA compositions could be blunting DHA’s beneficial effects. Therefore, we aimed to analyze the effects of a low PhA-concentrated DHA and a standard PhA-concentrated DHA in Apolipoprotein E knockout (ApoE−/−) mice. Behavioral tests and protein expression of pro-inflammatory, pro-oxidant, antioxidant factors, and AD-related mediators were evaluated. Low PhA-concentrated DHA decreased Aβ, ß-amyloid precursor protein (APP), p-tau, Ca2+/calmodulin-dependent protein kinase II (CAMKII), caspase 3, and catalase, and increased brain derived neurotrophic factor (BDNF) when compared to standard PhA-concentrated DHA. Low PhA-concentrated DHA decreased interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) protein expression in ApoE−/− mice when compared to standard PhA-concentrated DHA. No significant differences were found in p22phox, inducible nitric oxide synthase (iNOS), glutathione peroxidase (GPx), superoxide dismutase 1 (SOD-1), and tau protein expression. The positive actions of a low PhA-concentrated DHA were functionally reflected by improving the cognitive deficit in the AD experimental model. Therefore, reduction of PhA content in DHA compositions could highlight a novel pathway for the neurodegeneration processes related to AD.
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Zhu J, Xiang YB, Cai H, Li H, Gao YT, Zheng W, Shu XO. A Prospective Investigation of Dietary Intake and Functional Impairments Among the Elderly. Am J Epidemiol 2018; 187:2372-2386. [PMID: 30060001 DOI: 10.1093/aje/kwy156] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 07/23/2018] [Indexed: 01/06/2023] Open
Abstract
Limited information is available in Asian populations regarding the association of dietary intake and patterns with age-related functional impairments. Using data from 2 population-based cohort studies in China, the Shanghai Women's Health Study (1996-2015) and Shanghai Men's Health Study (2002-2015), we prospectively examined adherence to dietary guidelines, including the Chinese Food Pagoda, the Dietary Approaches to Stop Hypertension, and the Alternative Healthy Eating Index, as well as consumption of specific foods, for their associations with impairment in function, both physical (walking, hearing/vision) and mental (memory, decision-making). Included in the analyses were 30,484 participants who had been followed for an average of 14.4 years and were between the ages of 70 and 86 years at the functional status assessment. Higher dietary-recommendation adherence scores were associated with a lower likelihood of developing functional impairments. The odds ratios ranged from 0.61 (95% confidence interval: 0.54, 0.70) to 0.83 (95% confidence interval: 0.72, 0.95) when extreme quintiles were compared. Higher fish, poultry, vegetable, and fruit intake, moderate red meat intake, and low rice consumption were associated with a reduced probability of having physical or mental impairments. Our findings highlight the importance of a high-quality diet in maintaining functional status among the aged population.
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Affiliation(s)
- Jingjing Zhu
- Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Yong-Bing Xiang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Hui Cai
- Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Honglan Li
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yu-Tang Gao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Wei Zheng
- Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Xiao-Ou Shu
- Vanderbilt Epidemiology Center, Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
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Catani MV, Gasperi V, Bisogno T, Maccarrone M. Essential Dietary Bioactive Lipids in Neuroinflammatory Diseases. Antioxid Redox Signal 2018; 29:37-60. [PMID: 28637354 PMCID: PMC5984567 DOI: 10.1089/ars.2016.6958] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 06/19/2017] [Accepted: 06/20/2017] [Indexed: 12/13/2022]
Abstract
SIGNIFICANCE Under physiological conditions, neurons and glia are in a healthy, redox-balanced environment; when injury perturbs this equilibrium, a neuroinflammatory state is established by activated microglia that triggers pro-inflammatory responses and alters the oxidant/antioxidant balance, thus leading to neuronal loss and neurodegeneration. In neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyothrophic lateral sclerosis, and multiple sclerosis), the brain is in a constitutively self-sustaining cycle of inflammation and oxidative stress that prompts and amplifies brain damage. Recent Advances: Recently, an increasing amount of scientific data highlight the ability of specific nutrients to cross the blood-brain barrier, and to modulate inflammatory and oxidative pathways. Therefore, nutritional approaches may contribute to restore the lost equilibrium among factors accounting for neurodegeneration. CRITICAL ISSUES Herein, we critically examine how essential lipids (including fatty acids, liposoluble vitamins and phytosterols) might contribute to accelerate or prevent the onset and progression of such pathologies. In particular, we highlight that experimental and clinical findings, although promising, are still inadequate to draw definitive conclusions. FUTURE DIRECTIONS More research is warranted in order to establish the real impact of lipid intake on brain health, especially when redox balance and inflammatory responses have been already compromised. In the future, it would be hoped to gain a detailed knowledge of chemical modifications and dynamic properties of such nutrients, before planning to exploit them as potential therapeutics. Antioxid. Redox Signal. 29, 37-60.
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Affiliation(s)
- Maria Valeria Catani
- Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy
| | - Valeria Gasperi
- Department of Experimental Medicine and Surgery, Tor Vergata University of Rome, Rome, Italy
| | - Tiziana Bisogno
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mauro Maccarrone
- Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
- European Center for Brain Research/Santa Lucia Foundation IRCCS, Rome, Italy
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Samieri C, Morris MC, Bennett DA, Berr C, Amouyel P, Dartigues JF, Tzourio C, Chasman DI, Grodstein F. Fish Intake, Genetic Predisposition to Alzheimer Disease, and Decline in Global Cognition and Memory in 5 Cohorts of Older Persons. Am J Epidemiol 2018; 187:933-940. [PMID: 29053784 DOI: 10.1093/aje/kwx330] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 10/03/2017] [Indexed: 11/13/2022] Open
Abstract
Fish are a primary source of long-chain omega-3 fatty acids, which may help delay cognitive aging. We pooled participants from the French Three-City study and 4 US cohorts (Nurses' Health Study, Women's Health Study, Chicago Health and Aging Project, and Rush Memory and Aging Project) for whom diet and cognitive data were available (n = 23,688 white persons, aged ≥65 years, 88% female, baseline year range of 1992-1999, and median follow-up range of 3.9-9.1 years) to investigate the relationship of fish intake to cognitive decline and examine interactions with genes related to Alzheimer disease. We estimated cohort-specific associations between fish and change in composite scores of global cognition and episodic memory using linear mixed models, and we pooled results using inverse-variance weighted meta-analysis. In multivariate analyses, higher fish intake was associated with slower decline in both global cognition and memory (P for trend ≤ 0.031). Consuming ≥4 servings/week versus <1 serving/week of fish was associated with a lower rate of memory decline: 0.018 (95% confidence interval: 0.004, 0.032) standard units, an effect estimate equivalent to that found for 4 years of age. For global cognition, no comparisons of higher versus low fish intake reached statistical significance. In this meta-analysis, higher fish intake was associated with a lower rate of memory decline. We found no evidence of effect modification by genes associated with Alzheimer disease.
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Affiliation(s)
- Cécilia Samieri
- Bordeaux Population Health Research Center, Institut National de la Santé et de la Recherche Médicale, U1219, and University of Bordeaux, Bordeaux, France
| | - Martha-Clare Morris
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - David A Bennett
- Department of Behavioral Sciences, Department of Neurology and the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
| | - Claudine Berr
- Neuropsychiatrie: Recherche Epidémiologique et Clinique, Institut National de la Santé et de la Recherche Médicale, U1061, and Université de Montpellier, Montpellier, France
| | - Philippe Amouyel
- Institut Pasteur de Lille, Institut National de la Santé et de la Recherche Médicale, U1167, and Université Lille-Nord de France, Lille, France
| | - Jean-François Dartigues
- Bordeaux Population Health Research Center, Institut National de la Santé et de la Recherche Médicale, U1219, and University of Bordeaux, Bordeaux, France
| | - Christophe Tzourio
- Bordeaux Population Health Research Center, Institut National de la Santé et de la Recherche Médicale, U1219, and University of Bordeaux, Bordeaux, France
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Francine Grodstein
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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Hadad N, Levy R. Combination of EPA with Carotenoids and Polyphenol Synergistically Attenuated the Transformation of Microglia to M1 Phenotype Via Inhibition of NF-κB. Neuromolecular Med 2017; 19:436-451. [PMID: 28779377 DOI: 10.1007/s12017-017-8459-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 07/31/2017] [Indexed: 12/13/2022]
Abstract
Microglia activation toward the M1 phenotype has been reported to contribute to the neurodegenerative processes and cognition alterations due to the release of pro-inflammatory mediators and cytokines. The aim of the present research was to assess the effectiveness of free fatty acids omega-3 preparations: eicosapentaenoic acid (EPA) or/and docosahexaenoic acid (DHA), carotenoids and phenolics combinations, in inhibiting the release of inflammatory mediators from activated microglia. Preincubation of BV-2 microglia cells with each of the FFAs omega-3 preparations in a range of 0.03-2 μM together with Lyc-O-mato® (0.1 μM), Carnosic acid (0.2 μM) with or without Lutein (0.2 μM), 1 h before addition of lipopolysaccharide (LPS) for 16 h caused a synergistic inhibition of nitric oxide (NO) production with a rank order of EPA > Ropufa (EPA/DHA 2/1) > Krill (EPA/DHA 1.23/1). The optimal inhibitory combinations of EPA (0.125 μM) with the phytonutrients caused a synergistic inhibition of prostaglandin E2 (PGE2) release, IL-6 secretion, superoxide and NO production and prevention of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) upregulation and elevated CD40 expression in microglia exposed to LPS or interferon-γ (IFN-γ), representing infection or inflammation, respectively. The presence of the combination caused a synergistic increase in the release of the anti-inflammatory cytokine IL-10. The inhibitory effects by the combinations of EPA with the phytonutrients were mediated by the inhibition of the redox-sensitive NF-κB activation and detected by its phosphorylated p-65 on serine 536 in microglia stimulated by either LPS or IFN-γ. In addition, phosphorylated CREB on serine 133 which was shown to be involved in the induction of iNOS was inhibited by the combinations in stimulated cells. In conclusion, the results suggest that low concentrations of EPA with the phytonutrients are very efficient in inhibiting the transformation of microglia to M1 phenotype and may prevent cognition deficit.
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Affiliation(s)
- Nurit Hadad
- Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Soroka University Medical Center and Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel
| | - Rachel Levy
- Infectious Diseases Laboratory, Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Soroka University Medical Center and Ben-Gurion University of the Negev, 84105, Beer-Sheva, Israel.
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Yassine HN, Braskie MN, Mack WJ, Castor KJ, Fonteh AN, Schneider LS, Harrington MG, Chui HC. Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers: A Review. JAMA Neurol 2017; 74:339-347. [PMID: 28114437 DOI: 10.1001/jamaneurol.2016.4899] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Importance The apolipoprotein E ε4 (APOE4) allele identifies a unique population that is at significant risk for developing Alzheimer disease (AD). Docosahexaenoic acid (DHA) is an essential ω-3 fatty acid that is critical to the formation of neuronal synapses and membrane fluidity. Observational studies have associated ω-3 intake, including DHA, with a reduced risk for incident AD. In contrast, randomized clinical trials of ω-3 fatty acids have yielded mixed and inconsistent results. Interactions among DHA, APOE genotype, and stage of AD pathologic changes may explain the mixed results of DHA supplementation reported in the literature. Observations Although randomized clinical trials of ω-3 in symptomatic AD have had negative findings, several observational and clinical trials of ω-3 in the predementia stage of AD suggest that ω-3 supplementation may slow early memory decline in APOE4 carriers. Several mechanisms by which the APOE4 allele could alter the delivery of DHA to the brain may be amenable to DHA supplementation in predementia stages of AD. Evidence of accelerated DHA catabolism (eg, activation of phospholipases and oxidation pathways) could explain the lack of efficacy of ω-3 supplementation in AD dementia. The association of cognitive benefit with DHA supplementation in predementia but not AD dementia suggests that early ω-3 supplementation may reduce the risk for or delay the onset of AD symptoms in APOE4 carriers. Recent advances in brain imaging may help to identify the optimal timing for future DHA clinical trials. Conclusions and Relevance High-dose DHA supplementation in APOE4 carriers before the onset of AD dementia can be a promising approach to decrease the incidence of AD. Given the safety profile, availability, and affordability of DHA supplements, refining an ω-3 intervention in APOE4 carriers is warranted.
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Affiliation(s)
- Hussein N Yassine
- Division of Endocrinology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles
| | - Meredith N Braskie
- Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey
| | - Wendy J Mack
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
| | - Katherine J Castor
- Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California
| | - Alfred N Fonteh
- Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California
| | - Lon S Schneider
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles6Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles
| | - Michael G Harrington
- Department of Neurosciences, Huntington Medical Research Institutes, Pasadena, California
| | - Helena C Chui
- Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles
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Cutuli D. Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging. Curr Neuropharmacol 2017; 15:534-542. [PMID: 27306037 PMCID: PMC5543674 DOI: 10.2174/1570159x14666160614091311] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Revised: 05/16/2016] [Accepted: 05/31/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Omega-3 polyunsaturated fatty acids (n-3 PUFA) are structural components of the brain and are indispensable for neuronal membrane synthesis. Along with decline in cognition, decreased synaptic density and neuronal loss, normal aging is accompanied by a reduction in n-3 PUFA concentration in the brain in both humans and rodents. Recently, many clinical and experimental studies have demonstrated the importance of n-3 PUFA in counteracting neurodegeneration and agerelated dysfunctions. METHODS This review will focus on the neuroprotective effects of n-3 PUFA on cognitive impairment, neuroinflammation and neurodegeneration during normal aging. Multiple pathways of n-3 PUFA preventive action will be examined. RESULTS Namely, n-3 PUFA have been shown to increase the levels of several signaling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses as well as the enhancement of hippocampal neurogenesis even at old age. In elderly subjects n-3 PUFA exert anti-inflammatory effects associated with improved cognitive functions. Interestingly, growing evidence highlights n-3 PUFA efficacy in preventing the loss of both gray and white matter volume and integrity. CONCLUSION This review shows that n-3 PUFA are essential for a successful aging and appear as ideal cognitive enhancers to be implemented in nutritional interventions for the promotion of healthy aging.
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Affiliation(s)
- Debora Cutuli
- Fondazione Santa Lucia of Rome, Via del Fosso di Fiorano 64, 00143 Rome, Italy
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The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer's disease. ALZHEIMERS RESEARCH & THERAPY 2016; 8:25. [PMID: 27358067 PMCID: PMC4928349 DOI: 10.1186/s13195-016-0194-x] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 06/06/2016] [Indexed: 01/01/2023]
Abstract
Background Apolipoprotein E (APOE) ɛ4 and low cerebrospinal fluid (CSF) amyloid-β42 (Aβ42) levels are predictors for developing Alzheimer’s disease (AD). The results of several studies indicate an interaction between docosahexaenoic acid (DHA) consumption and cognitive outcomes by APOE genotype. Our objective in the present study was to examine whether APOE ɛ4 genotype and low CSF Aβ42 levels were associated with reduced delivery of DHA to CSF in the Alzheimer’s Disease Cooperative Study-sponsored DHA clinical trial. Methods Phospholipid DHA was assayed in the plasma of 384 participants and CSF of 70 participants at baseline. Forty-four of the 70 participants completed the 18-month follow-up visit after allocation to placebo (n = 15) or DHA (n = 29). Plasma and CSF DHA levels, CSF Aβ42, Tau, and phosphorylated Tau were measured at baseline and after the 18-month intervention. Participants were divided into tertiles based on baseline Aβ42 CSF levels. To assess DHA delivery across the blood-brain barrier, the ratio of CSF to plasma DHA levels was calculated. Results At baseline, there were no significant differences between CSF or plasma phospholipid DHA levels by CSF Aβ42 tertiles or ɛ4 status. After 18 months of DHA supplementation, participants at the lowest Aβ42 tertile had significantly lower CSF DHA levels (p = 0.01) and lower CSF-to-plasma DHA ratios (p = 0.05) compared to the other tertiles. Baseline CSF Aβ42 levels were significantly lower in ɛ4 carriers than in ɛ4 noncarriers (p = 0.01). Participants carrying the ɛ4 allele (n = 25) demonstrated a less pronounced increase in CSF DHA level compared with noncarriers (n = 4), with a possible interaction effect between treatment and APOE genotype (p = 0.07). Conclusions APOE ɛ4 allele and lower CSF Aβ42 levels were associated with less transport of DHA to CSF. Brain amyloid pathology may limit the delivery of DHA to the brain in AD. Trial Registration Clinicaltrials.gov identifier: NCT00440050. Registered on 22 Feb 2007.
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Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N. Global survey of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res 2016; 63:132-52. [PMID: 27216485 DOI: 10.1016/j.plipres.2016.05.001] [Citation(s) in RCA: 355] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 05/14/2016] [Accepted: 05/18/2016] [Indexed: 02/05/2023]
Abstract
Studies reporting blood levels of the omega-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were systematically identified in order to create a global map identifying countries and regions with different blood levels. Included studies were those of healthy adults, published in 1980 or later. A total of 298 studies met all inclusion criteria. Studies reported fatty acids in various blood fractions including plasma total lipids (33%), plasma phospholipid (32%), erythrocytes (32%) and whole blood (3.0%). Fatty acid data from each blood fraction were converted to relative weight percentages (wt.%) and then assigned to one of four discrete ranges (high, moderate, low, very low) corresponding to wt.% EPA+DHA in erythrocyte equivalents. Regions with high EPA+DHA blood levels (>8%) included the Sea of Japan, Scandinavia, and areas with indigenous populations or populations not fully adapted to Westernized food habits. Very low blood levels (≤4%) were observed in North America, Central and South America, Europe, the Middle East, Southeast Asia, and Africa. The present review reveals considerable variability in blood levels of EPA+DHA and the very low to low range of blood EPA+DHA for most of the world may increase global risk for chronic disease.
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Affiliation(s)
- Ken D Stark
- University of Waterloo, Department of Kinesiology, 200 University Avenue, Waterloo, ON, N2L 3G1, Canada.
| | - Mary E Van Elswyk
- Scientific Affairs, Van Elswyk Consulting, Inc., 10350 Macedonia St., Longmont, CO 80503, USA.
| | - M Roberta Higgins
- MEDetect Clinical Information Associates, Inc., PO Box 152, Skippack, PA 19474, USA.
| | | | - Norman Salem
- DSM Nutritional Products Ltd., 6480 Dobbin Road, Columbia, MD 21045, USA.
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Human apolipoprotein E allele and docosahexaenoic acid intake modulate peripheral cholesterol homeostasis in mice. J Nutr Biochem 2016; 34:83-8. [PMID: 27239755 DOI: 10.1016/j.jnutbio.2016.05.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 04/25/2016] [Accepted: 05/03/2016] [Indexed: 11/22/2022]
Abstract
Carrying at least one apolipoprotein E ε4 allele (E4+) is the main genetic risk factor for Alzheimer's disease (AD). Epidemiological studies support that consuming fatty fish rich in docosahexaenoic acid (DHA; 22:6ω3) is protective against development of AD. However, this protective effect seems not to hold in E4+. The involvement of APOE genotype on the relationship between DHA intake and cognitive decline could be mediated through cholesterol. Many studies show a link between cholesterol metabolism and AD progression. In this study, we investigated whether cholesterol metabolism is improved in E3+ and E4+ mice consuming a diet rich in DHA. Plasma cholesterol was 36% lower in E4+ mice compared to E3+ mice fed the control diet (P=.02), and in the liver, there was a significant genotype effect where cholesterol levels were 18% lower in E4+ mice than E3+ mice. The low-density lipoprotein receptor was overexpressed in the liver of E4+ mice. Plasma cholesterol levels were 33% lower after the DHA diet (P=.02) in E3+ mice only, and there was a significant diet effect where cholesterol level was 67% lower in the liver of mice fed DHA. Mice fed the DHA diet also had 62% less lipolysis stimulated lipoprotein receptor expression in the liver compared to mice fed the control diet (P<.0001), but there was no genotype effect. These findings suggest that plasma and liver cholesterol homeostasis and the receptors regulating uptake of cholesterol in the liver are modulated differently and independently by APOE allele and DHA intake.
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van de Rest O, Wang Y, Barnes LL, Tangney C, Bennett DA, Morris MC. APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline. Neurology 2016; 86:2063-70. [PMID: 27164694 DOI: 10.1212/wnl.0000000000002719] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 02/03/2016] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To examine the association between consumption of seafood and long-chain n-3 fatty acids with change in 5 cognitive domains over an average of 4.9 years. METHODS From an ongoing longitudinal, community-based epidemiologic study of aging and dementia (the Rush Memory and Aging Project), we included 915 participants (age 81.4 ± 7.2 years, 25% men) who had completed at least one follow-up cognitive assessment and dietary data. Diet was assessed by semiquantitative food frequency questionnaire. Scores for global cognitive function and 5 cognitive domains (episodic, semantic, and working memory, perceptual speed, and visuospatial ability) were assessed using 19 cognitive tests. Mixed models adjusted for multiple risk factors of cognitive change were used to assess the associations. RESULTS Consumption of seafood was associated with slower decline in semantic memory (β = 0.024; p = 0.03) and perceptual speed (β = 0.020; p = 0.05) in separate models adjusted for age, sex, education, participation in cognitive activities, physical activity, alcohol consumption, smoking, and total energy intake. In secondary analyses, APOE ε4 carriers demonstrated slower rates of decline in global cognition and in multiple cognitive domains with weekly seafood consumption and with moderate to high long-chain n-3 fatty acid intake from food. These associations were not present in APOE ε4 noncarriers. Higher intake levels of α-linolenic acid were associated with slower global cognitive decline, but also only in APOE ε4 carriers. CONCLUSIONS These results suggest protective relations of one meal per week of seafood and long-chain n-3 fatty acids against decline in multiple cognitive domains. The role of APOE ε4 in this association needs further study.
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Affiliation(s)
- Ondine van de Rest
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL.
| | - Yamin Wang
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL
| | - Lisa L Barnes
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL
| | - Christine Tangney
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL
| | - David A Bennett
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL
| | - Martha Clare Morris
- From the Division of Human Nutrition (O.v.d.R.), Wageningen University, the Netherlands; and Department of Internal Medicine, Section on Nutrition and Nutritional Epidemiology (Y.W., M.C.M.), Rush Alzheimer's Disease Center (L.L.B., D.A.B.), Department of Behavioral Sciences (L.L.B.), Department of Clinical Nutrition (C.T.), and Department of Neurology (D.A.B.), Rush University Medical Center, Chicago, IL
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EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). DHA and improvement of memory function: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006. EFSA J 2016. [DOI: 10.2903/j.efsa.2016.4455] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Cutuli D, Pagani M, Caporali P, Galbusera A, Laricchiuta D, Foti F, Neri C, Spalletta G, Caltagirone C, Petrosini L, Gozzi A. Effects of Omega-3 Fatty Acid Supplementation on Cognitive Functions and Neural Substrates: A Voxel-Based Morphometry Study in Aged Mice. Front Aging Neurosci 2016; 8:38. [PMID: 26973513 PMCID: PMC4777728 DOI: 10.3389/fnagi.2016.00038] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 02/15/2016] [Indexed: 11/13/2022] Open
Abstract
Human and experimental studies have revealed putative neuroprotective and pro-cognitive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in aging, evidencing positive correlations between peripheral n-3 PUFA levels and regional grey matter (GM) volume, as well as negative correlations between dietary n-3 PUFA levels and cognitive deficits. We recently showed that n-3 PUFA supplemented aged mice exhibit better hippocampal-dependent mnesic functions, along with enhanced cellular plasticity and reduced neurodegeneration, thus supporting a role of n-3 PUFA supplementation in preventing cognitive decline during aging. To corroborate these initial results and develop new evidence on the effects of n-3 PUFA supplementation on brain substrates at macro-scale level, here we expanded behavioral analyses to the emotional domain (anxiety and coping skills), and carried out a fine-grained regional GM volumetric mapping by using high-resolution MRI-based voxel-based morphometry. The behavioral effects of 8 week n-3 PUFA supplementation were measured on cognitive (discriminative, spatial and social) and emotional (anxiety and coping) abilities of aged (19 month-old at the onset of study) C57B6/J mice. n-3 PUFA supplemented mice showed better mnesic performances as well as increased active coping skills. Importantly, these effects were associated with enlarged regional hippocampal, retrosplenial and prefrontal GM volumes, and with increased post mortem n-3 PUFA brain levels. These findings indicate that increased dietary n-3 PUFA intake in normal aging can improve fronto-hippocampal GM structure and function, an effect present also when the supplementation starts at late age. Our data are consistent with a protective role of n-3 PUFA supplementation in counteracting cognitive decline, emotional dysfunctions and brain atrophy.
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Affiliation(s)
- Debora Cutuli
- Santa Lucia FoundationRome, Italy; University of Rome "Sapienza"Rome, Italy
| | - Marco Pagani
- Functional Neuroimaging Laboratory, Istituto Italiano di TecnologiaRovereto, Italy; Center for Mind and Brain Sciences, University of TrentoRovereto, Italy
| | - Paola Caporali
- Santa Lucia FoundationRome, Italy; University of Rome "Sapienza"Rome, Italy
| | - Alberto Galbusera
- Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia Rovereto, Italy
| | | | - Francesca Foti
- Santa Lucia FoundationRome, Italy; University of Rome "Sapienza"Rome, Italy
| | | | | | - Carlo Caltagirone
- Santa Lucia FoundationRome, Italy; University of Rome "Tor Vergata"Rome, Italy
| | - Laura Petrosini
- Santa Lucia FoundationRome, Italy; University of Rome "Sapienza"Rome, Italy
| | - Alessandro Gozzi
- Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia Rovereto, Italy
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Morris MC, Brockman J, Schneider JA, Wang Y, Bennett DA, Tangney CC, van de Rest O. Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults. JAMA 2016; 315:489-97. [PMID: 26836731 PMCID: PMC5460535 DOI: 10.1001/jama.2015.19451] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
IMPORTANCE Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (ρ = 0.16; P = .02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal[s]/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (β = -0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (β = -0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (β = -0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE ε4) carriers. Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.
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Affiliation(s)
- Martha Clare Morris
- Section on Nutrition and Nutritional Epidemiology, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | | | - Julie A Schneider
- Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, Illinois4Department of Neurology, Rush University Medical Center, Chicago, Illinois5Department of Pathology, Rush University Medical Center, Chicago, Illinois
| | - Yamin Wang
- Section on Nutrition and Nutritional Epidemiology, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - David A Bennett
- Rush Alzheimer Disease Center, Rush University Medical Center, Chicago, Illinois4Department of Neurology, Rush University Medical Center, Chicago, Illinois
| | - Christy C Tangney
- Department of Clinical Nutrition, Rush University Medical Center, Chicago, Illinois
| | - Ondine van de Rest
- Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
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Layé S, Madore C, St-Amour I, Delpech JC, Joffre C, Nadjar A, Calon F. N-3 polyunsaturated fatty acid and neuroinflammation in aging and Alzheimer’s disease. ACTA ACUST UNITED AC 2015. [DOI: 10.3233/nua-150049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Sophie Layé
- Nutrition et Neurobiologie Intégrée, Bordeaux Cedex, France
- University of Bordeaux, Bordeaux, France
- OptiNutriBrain International associated Laboratory (NutriNeuro France-INAF Canada)
| | - Charlotte Madore
- Nutrition et Neurobiologie Intégrée, Bordeaux Cedex, France
- University of Bordeaux, Bordeaux, France
| | - Isabelle St-Amour
- Faculté de Pharmacie, Université Laval; Centre de Recherche du CHU de Québec, Québec, Canada
| | - Jean-Christophe Delpech
- Nutrition et Neurobiologie Intégrée, Bordeaux Cedex, France
- University of Bordeaux, Bordeaux, France
| | - Corinne Joffre
- Nutrition et Neurobiologie Intégrée, Bordeaux Cedex, France
- University of Bordeaux, Bordeaux, France
- OptiNutriBrain International associated Laboratory (NutriNeuro France-INAF Canada)
| | - Agnès Nadjar
- Nutrition et Neurobiologie Intégrée, Bordeaux Cedex, France
- University of Bordeaux, Bordeaux, France
- OptiNutriBrain International associated Laboratory (NutriNeuro France-INAF Canada)
| | - Frédéric Calon
- Faculté de Pharmacie, Université Laval; Centre de Recherche du CHU de Québec, Québec, Canada
- OptiNutriBrain International associated Laboratory (NutriNeuro France-INAF Canada)
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Dyall SC. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci 2015; 7:52. [PMID: 25954194 PMCID: PMC4404917 DOI: 10.3389/fnagi.2015.00052] [Citation(s) in RCA: 553] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 03/28/2015] [Indexed: 12/19/2022] Open
Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer’s disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.
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Affiliation(s)
- Simon C Dyall
- Faculty of Health and Social Sciences, Bournemouth University Bournemouth, UK
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Docosahexaenoic acid and adult memory: a systematic review and meta-analysis. PLoS One 2015; 10:e0120391. [PMID: 25786262 PMCID: PMC4364972 DOI: 10.1371/journal.pone.0120391] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 02/02/2015] [Indexed: 11/24/2022] Open
Abstract
Introduction Subjective memory complaints are common with aging. Docosahexaenoic acid (DHA; 22:6 n-3) is a long-chain polyunsaturated fatty acid (LCPUFA) and an integral part of neural membrane phospholipids that impacts brain structure and function. Past research demonstrates a positive association between DHA plasma status/dietary intake and cognitive function. Objectives The current meta-analysis was designed to determine the effect of DHA intake, alone or combined with eicosapentaenoic acid (EPA; 20:5 n-3), on specific memory domains: episodic, working, and semantic in healthy adults aged 18 years and older. A secondary objective was to systematically review/summarize the related observational epidemiologic literature. Methods A systematic literature search of clinical trials and observational studies that examined the relationship between n-3 LCPUFA on memory outcomes in healthy adults was conducted in Ovid MEDLINE and EMBASE databases. Studies of subjects free of neurologic disease at baseline, with or without mild memory complaints (MMC), were included. Random effects meta-analyses were conducted to generate weighted group mean differences, standardized weighted group mean differences (Hedge’s g), z-scores, and p-values for heterogeneity comparing DHA/EPA to a placebo. A priori sub-group analyses were conducted to evaluate the effect of age at enrollment, dose level, and memory type tested. Results Episodic memory outcomes of adults with MMC were significantly (P<.004) improved with DHA/EPA supplementation. Regardless of cognitive status at baseline, > 1 g/day DHA/EPA improved episodic memory (P<.04). Semantic and working memory changes from baseline were significant with DHA but no between group differences were detected. Observational studies support a beneficial association between intake/blood levels of DHA/EPA and memory function in older adults. Conclusion DHA, alone or combined with EPA, contributes to improved memory function in older adults with mild memory complaints.
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Deckers K, van Boxtel MPJ, Schiepers OJG, de Vugt M, Muñoz Sánchez JL, Anstey KJ, Brayne C, Dartigues JF, Engedal K, Kivipelto M, Ritchie K, Starr JM, Yaffe K, Irving K, Verhey FRJ, Köhler S. Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. Int J Geriatr Psychiatry 2015; 30:234-46. [PMID: 25504093 DOI: 10.1002/gps.4245] [Citation(s) in RCA: 333] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 10/17/2014] [Accepted: 11/05/2014] [Indexed: 01/30/2023]
Abstract
OBJECTIVE Dementia has a multifactorial etiology, but the importance of individual health and lifestyle related risk factors is often uncertain or based on few studies. The goal of this paper is to identify the major modifiable risk factors for dementia as a first step in developing an effective preventive strategy and promoting healthy late life cognitive functioning. METHODS A mixed-method approach combined findings from a systematic literature review and a Delphi consensus study. The literature search was conducted in PubMed and updated an earlier review by the United States National Institutes of Health from 2010. We reviewed the available evidence from observational epidemiological studies. The online Delphi study asked eight international experts to rank and weigh each risk factor for its importance for dementia prevention. RESULTS Out of 3127 abstracts, 291 were included in the review. There was good agreement between modifiable risk factors identified in the literature review and risk factors named spontaneously by experts. After triangulation of both methods and re-weighting by experts, strongest support was found for depression, (midlife) hypertension, physical inactivity, diabetes, (midlife) obesity, hyperlipidemia, and smoking, while more research is needed for coronary heart disease, renal dysfunction, diet, and cognitive activity. CONCLUSIONS Findings provide good support for several somatic and lifestyle factors and will be used to inform the design of a new multicenter trial into dementia prevention.
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Affiliation(s)
- Kay Deckers
- Maastricht University, School for Mental Health and Neuroscience, Alzheimer Centrum Limburg, Maastricht, The Netherlands
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Abstract
PURPOSE OF REVIEW The literature on the influence of dietary omega-3 polyunsaturated fatty acid (ω-3 PUFA) on brain aging has grown exponentially during the last decade. Many avenues have been explored but no global picture or clear evidence has emerged. Experimental studies have shown that ω-3 PUFA is involved in many neurobiological processes that are involved in neurotransmission and neuroprotection, indicating that these PUFAs may prevent age-related brain damage. Human studies have revealed only a weak link between ω-3 PUFA status and cognitive aging, whereas interventional studies have yet to confirm it. The purpose of this review is to analyze the developments in the area during the last 2 years. RECENT FINDINGS Human brain MRI studies have confirmed previous findings that ω-3 PUFA can protect the brain during aging; two intervention studies obtained clear evidence. We also analyzed the experimental data clarifying the involvement of ω-3 PUFA in neurotransmission, neuroprotection (including prevention of peroxidation, inflammation, and excitotoxicity), and neurogenesis, thereby helping the brain cope with aging. SUMMARY These recent human and experimental studies provide support for and clarification of how ω-3 PUFA protect against brain aging and highlight the main lines for future research.
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Affiliation(s)
- Isabelle Denis
- aUnité de Neurobiologie de l'Olfaction, NBO U1197, INRA, Jouy-en-Josas bINSERM UMR 894, Centre de Psychiatrie et Neurosciences, Paris cUnité MICALIS, UMR 1319, INRA, Jouy-en-Josas dUnité NutriNeurO, UMR INRA 1286, Université Victor Segalen Bordeaux 2, Bordeaux, France
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Conway V, Larouche A, Alata W, Vandal M, Calon F, Plourde M. Apolipoprotein E isoforms disrupt long-chain fatty acid distribution in the plasma, the liver and the adipose tissue of mice. Prostaglandins Leukot Essent Fatty Acids 2014; 91:261-7. [PMID: 25301204 DOI: 10.1016/j.plefa.2014.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 08/28/2014] [Accepted: 09/16/2014] [Indexed: 11/17/2022]
Abstract
Evidences suggest that omega-3 fatty acid (n-3 PUFA) metabolism is imbalanced in apolipoprotein E epsilon 4 isoform carriers (APOE4). This study aimed to investigate APOE genotype-dependant modulation of FA profiles, protein and enzyme important to fatty acid (FA) metabolism in the adipose tissue, the liver and the plasma using human APOE-targeted replacement mouse-model (N=37). FA transport (FATP) and binding (FABP) protein levels in tissues and concentrations of liver carnitine palmitoyltransferase 1 (CPT1) were performed. N-3 PUFA concentration was >45% lower in the adipose tissue and liver of APOE4 mice compared to APOE3 mice. In APOE4 mice, there were higher levels of FATP and FABP in the liver and higher FATP in the adipose tissue compared to APOE2 mice. There was a trend towards higher CPT1 concentrations in APOE4 mice compared to APOE3 mice. Therefore, since APOE-isoform differences were not always in line with the unbalanced n-3 PUFA profiles in organs, other proteins may be involved in maintaining n-3 PUFA homeostasis in mice with different APOE-isoforms.
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Affiliation(s)
- Valérie Conway
- Research Center on Aging, Health and Social Services Center, University Institute of Geriatrics of Sherbrooke, Sherbrooke, Canada J1H 4C4; Departement of Medicine, Université de Sherbrooke, Sherbrooke, Canada; Institute of Nutrition and Functional Foods, Université Laval, Québec, Canada
| | - Annie Larouche
- Research Center on Aging, Health and Social Services Center, University Institute of Geriatrics of Sherbrooke, Sherbrooke, Canada J1H 4C4
| | - Wael Alata
- Faculty of pharmacy, Université Laval and CHU-Q Research Centre, Québec, Canada
| | - Milène Vandal
- Institute of Nutrition and Functional Foods, Université Laval, Québec, Canada; Faculty of pharmacy, Université Laval and CHU-Q Research Centre, Québec, Canada
| | - Frédéric Calon
- Institute of Nutrition and Functional Foods, Université Laval, Québec, Canada; Faculty of pharmacy, Université Laval and CHU-Q Research Centre, Québec, Canada
| | - Mélanie Plourde
- Research Center on Aging, Health and Social Services Center, University Institute of Geriatrics of Sherbrooke, Sherbrooke, Canada J1H 4C4; Departement of Medicine, Université de Sherbrooke, Sherbrooke, Canada; Institute of Nutrition and Functional Foods, Université Laval, Québec, Canada.
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Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat Rev Neurosci 2014; 15:771-85. [PMID: 25387473 DOI: 10.1038/nrn3820] [Citation(s) in RCA: 1028] [Impact Index Per Article: 93.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
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Chouinard-Watkins R, Plourde M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients 2014; 6:4452-71. [PMID: 25333200 PMCID: PMC4210928 DOI: 10.3390/nu6104452] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/02/2014] [Accepted: 09/24/2014] [Indexed: 01/01/2023] Open
Abstract
Apolipoprotein E (ApoE) is a protein playing a pivotal role in lipid homeostasis since it regulates cholesterol, triglyceride and phospholipid metabolism in the blood and the brain. APOE gene regulates the expression of this protein and has three different alleles: ε2, ε3 and ε4. Carrying an APOE4 allele is recognised as a genetic risk factor of late-onset Alzheimer’s disease (LOAD) and coronary heart disease (CHD). Consuming fatty fish, rich in long chain omega-3 fatty acids (LC omega-3), seems to be associated with risk reduction of developing LOAD and CHD but this link seems not to hold in APOE4 carriers, at least in LOAD. In CHD trials, APOE4 carriers supplemented with LC omega-3 were categorized as differential responders to the treatment with regards to CHD risk markers. This is potentially because fatty acid metabolism is disturbed in APOE4 carriers compared to the non-carriers. More specifically, homeostasis of LC omega-3 is disrupted in carriers of APOE4 allele and this is potentially because they β-oxidize more LC omega-3 than the non-carriers. Therefore, there is a potential shift in fatty acid selection for β-oxidation towards LC omega-3 which are usually highly preserved for incorporation into cell membranes.
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Affiliation(s)
- Raphaël Chouinard-Watkins
- Research Center on Aging, Health and Social Services Centre-University Institute of Geriatrics of Sherbrooke, Department of medicine, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, J1H 4C4, Canada.
| | - Mélanie Plourde
- Research Center on Aging, Health and Social Services Centre-University Institute of Geriatrics of Sherbrooke, Department of medicine, Université de Sherbrooke, 1036 Belvédère Sud, Sherbrooke, J1H 4C4, Canada.
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Joffre C, Nadjar A, Lebbadi M, Calon F, Laye S. n-3 LCPUFA improves cognition: the young, the old and the sick. Prostaglandins Leukot Essent Fatty Acids 2014; 91:1-20. [PMID: 24908517 DOI: 10.1016/j.plefa.2014.05.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 04/29/2014] [Accepted: 05/01/2014] [Indexed: 01/01/2023]
Abstract
Due to the implication of docosahexaenoic acid (DHA) in neurogenesis, synaptogenesis, neurite outgrowth and to its high incorporation into the brain, this n-3 long chain polyunsaturated fatty acid (LCPUFA) is considered as crucial in the development and maintenance of the learning memory performance throughout life. In the present chapter we aimed at reviewing data investigating the relation between DHA and cognition during the perinatal period, young adult- and adulthood and neurodegenerative diseases such as Alzheimer disease (AD). In Humans, dietary DHA supplementation from the perinatal period to adulthood does not reveal a clear and consistent memory improvement whereas it is the case in animal studies. The positive effects observed in animal models may have been enhanced by using n-3 PUFA deficient animal models as controls. In animal models of AD, a general consensus on the beneficial effects of n-3 LCPUFA in attenuating cognitive impairment was established. These studies make DHA a potential suitable micronutrient for the maintenance of cognitive performance at all periods of life.
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Affiliation(s)
- C Joffre
- Université Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France; INRA, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France.
| | - A Nadjar
- Université Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France; INRA, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France.
| | - M Lebbadi
- Centre de Recherche du CHUL, Axe Neurosciences, T2-05, 2705, Boulevard Laurier, Québec, QC, Canada G1V 4G2.
| | - F Calon
- Centre de Recherche du CHUL, Axe Neurosciences, T2-05, 2705, Boulevard Laurier, Québec, QC, Canada G1V 4G2.
| | - S Laye
- Université Bordeaux, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France; INRA, Nutrition and Integrative Neurobiology, UMR 1286, F-33000 Bordeaux, France.
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Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health 2014; 14:643. [PMID: 24962204 PMCID: PMC4099157 DOI: 10.1186/1471-2458-14-643] [Citation(s) in RCA: 508] [Impact Index Per Article: 46.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 05/13/2014] [Indexed: 12/15/2022] Open
Abstract
Background Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer’s disease (AD) is the most frequent cause of dementia, increasing in prevalence from <1% below the age of 60 years to >40% above 85 years of age. Methods We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias. Results In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from ~38.9% for caffeine to ~89% for physical activity. Education also had a significantly higher propensity for “a positive finding” compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%=31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found. Conclusions Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of incident AD. Further studies are needed to support other potential modifiable protective factors, such as caffeine.
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Affiliation(s)
- May A Beydoun
- Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIA/NIH/IRP, 251 Bayview Blvd,, Suite 100, Room #: 04B118, Baltimore, MD 21224, USA.
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Abstract
The vast majority of Alzheimer's disease (AD) cases are late onset (LOAD), which is genetically complex with heritability estimates up to 80%. Apolipoprotein E (APOE) has been irrefutably recognized as the major genetic risk factor, with semidominant inheritance, for LOAD. Although the mechanisms that underlie the pathogenic nature of APOE in AD are still not completely understood, emerging data suggest that APOE contributes to AD pathogenesis through both amyloid-β (Aβ)-dependent and Aβ-independent pathways. Given the central role for APOE in the modulation of AD pathogenesis, many therapeutic strategies have emerged, including converting APOE conformation, regulating APOE expression, mimicking APOE peptides, blocking the APOE/Aβ interaction, modulating APOE lipidation state, and gene therapy. Accumulating evidence also suggests the utility of APOE genotyping in AD diagnosis, risk assessment, prevention, and treatment response.
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Affiliation(s)
- Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao 266071, China; ,
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Vandal M, Alata W, Tremblay C, Rioux-Perreault C, Salem N, Calon F, Plourde M. Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2. J Neurochem 2014; 129:516-26. [PMID: 24345162 DOI: 10.1111/jnc.12640] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Revised: 12/12/2013] [Accepted: 12/12/2013] [Indexed: 12/27/2022]
Abstract
Benefits on cognition from docosahexaenoic acid (DHA, 22 : 6 n-3) intake are absent in humans carrying apolipoprotein E ε4 allele (APOE4), the most important genetic risk factor for Alzheimer's disease (AD). To test the hypothesis that carrying APOE4 impairs DHA distribution, we evaluated plasma and brain fatty acid profiles and uptake of [(14) C]-DHA using in situ cerebral perfusion through the blood-brain barrier in 4- and 13-month-old male and female APOE-targeted replacement mice (APOE2, APOE3, and APOE4), fed with a DHA-depleted diet. Cortical and plasma DHA were 9% lower and 34% higher in APOE4 compared to APOE2 mice, respectively. Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice. A significant relationship was established between DHA and apoE concentrations in the cortex of mice (r(2) = 0.21) and AD patients (r(2) = 0.32). Altogether, our results suggest that lower brain uptake of DHA in APOE4 than in APOE2 mice may limit the accumulation of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of AD. Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD).
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Affiliation(s)
- Milène Vandal
- Centre de recherche du centre Hospitalier de l'Université Laval (CHUL), Québec City, Québec, Canada; Institut des Nutraceutiques et des Aliments Fonctionnels, Université Laval, Québec City, Québec, Canada
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Barberger-Gateau P, Samieri C, Feart C, Cunnane SC. Nutrition and Cognitive Decline in Older Persons: Bridging the Gap Between Epidemiology and Intervention Studies. PHARMA-NUTRITION 2014. [DOI: 10.1007/978-3-319-06151-1_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Bowman GL, Dodge HH, Mattek N, Barbey AK, Silbert LC, Shinto L, Howieson DB, Kaye JA, Quinn JF. Plasma omega-3 PUFA and white matter mediated executive decline in older adults. Front Aging Neurosci 2013; 5:92. [PMID: 24379780 PMCID: PMC3863786 DOI: 10.3389/fnagi.2013.00092] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2013] [Accepted: 11/27/2013] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Cross-sectional studies have identified long chain omega-3 polyunsaturated fatty acids (eicosapentaenoic acid 20:5n-3 and docosahexaenoic acid 22:6n-3 (O3PUFA) in association with fewer white matter lesions and better executive function in older adults. We hypothesized that O3PUFA are associated with less executive decline over time and that total white matter hyperintensity volume (WMH) mediates this association. METHODS Eighty-six non-demented older adults were followed over 4 years after measurement of plasma O3PUFA with annual evaluations of cognitive function. A subset of these participants also had brain MRI of total WMH available to conduct a formal mediation analysis of a putative relationship between O3PUFA and cognitive function. RESULTS Mean age at baseline was 86, 62% were female and 11% carried the APOE4 allele. Each 100 μg/ml increase in plasma O3PUFA associated with 4 s less change in executive decline per year of aging (p = 0.02, fully adjusted model). O3PUFA was not associated with verbal memory or global cognitive changes. The significance of the association between O3PUFA and better executive function was lost once WMH was added to the regression model. CONCLUSION Executive decline with age appears to be a cognitive domain particularly sensitive to plasma O3PUFA in longitudinal examination. O3PUFA may modulate executive functioning by mechanisms underlying the development of WMH, a biologically plausible hypothesis that warrants further investigation.
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Affiliation(s)
- Gene L Bowman
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Hiroko H Dodge
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Nora Mattek
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Aron K Barbey
- Beckman Institute for Advanced Science and Technology Urbana, IL, USA
| | - Lisa C Silbert
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Lynne Shinto
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Diane B Howieson
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Jeffrey A Kaye
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
| | - Joseph F Quinn
- Brain Institute, Department of Neurology, Oregon Health and Science University Portland, OR, USA
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Koivisto H, Grimm MO, Rothhaar TL, Berkecz R, Lütjohann D D, Giniatullina R, Takalo M, Miettinen PO, Lahtinen HM, Giniatullin R, Penke B, Janáky T, Broersen LM, Hartmann T, Tanila H. Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition. J Nutr Biochem 2013; 25:157-69. [PMID: 24445040 DOI: 10.1016/j.jnutbio.2013.09.015] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 08/30/2013] [Accepted: 09/11/2013] [Indexed: 11/15/2022]
Abstract
Dietary fish oil, providing n3 polyunsaturated fatty acids like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), associates with reduced dementia risk in epidemiological studies and reduced amyloid accumulation in Alzheimer mouse models. We now studied whether additional nutrients can improve the efficacy of fish oil in alleviating cognitive deficits and amyloid pathology in APPswe/PS1dE9 transgenic and wild-type mice. We compared four isocaloric (5% fat) diets. The fish oil diet differed from the control diet only by substituted fish oil. Besides fish oil, the plant sterol diet was supplemented with phytosterols, while the Fortasyn diet contained as supplements precursors and cofactors for membrane synthesis, viz. uridine-monophosphate; DHA and EPA; choline; folate; vitamins B6, B12, C and E; phospholipids and selenium. Mice began the special diets at 5 months and were sacrificed at 14 months after behavioral testing. Transgenic mice, fed with control chow, showed poor spatial learning, hyperactivity in exploring a novel cage and reduced preference to explore novel odors. All fish-oil-containing diets increased exploration of a novel odor over a familiar one. Only the Fortasyn diet alleviated the spatial learning deficit. None of the diets influenced hyperactivity in a new environment. Fish-oil-containing diets strongly inhibited β- and γ-secretase activity, and the plant sterol diet additionally reduced amyloid-β 1-42 levels. These data indicate that beneficial effects of fish oil on cognition in Alzheimer model mice can be enhanced by adding other specific nutrients, but this effect is not necessarily mediated via reduction of amyloid accumulation.
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Affiliation(s)
- Hennariikka Koivisto
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Marcus O Grimm
- Experimental Neurology, Saarland University, Homburg/Saar 66123, Germany; Deutsches Institut für Demenz Prävention, Saarland University, Homburg/Saar 66421, Germany
| | - Tatjana L Rothhaar
- Experimental Neurology, Saarland University, Homburg/Saar 66123, Germany
| | - Róbert Berkecz
- Department Medical Chemistry, University of Szeged, Szeged 6720, Hungary
| | - Dieter Lütjohann D
- Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53113, Germany
| | - Rajsa Giniatullina
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Mari Takalo
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Pasi O Miettinen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Hanna-Maija Lahtinen
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Rashid Giniatullin
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland
| | - Botond Penke
- Department Medical Chemistry, University of Szeged, Szeged 6720, Hungary
| | - Tamás Janáky
- Department Medical Chemistry, University of Szeged, Szeged 6720, Hungary
| | - Laus M Broersen
- Danone Research Centre for Specialised Nutrition, Wageningen 6700 CA, The Netherlands
| | - Tobias Hartmann
- Deutsches Institut für Demenz Prävention, Saarland University, Homburg/Saar 66421, Germany
| | - Heikki Tanila
- A. I. Virtanen Institute, University of Eastern Finland, Kuopio FI-70211, Finland; Department of Neurology, Kuopio University Hospital, Kuopio FI-70211, Finland.
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Abstract
Epidemiological studies fairly convincingly suggest that higher intakes of fatty fish and n-3 fatty acids are associated with reduced risk of Alzheimer's disease (AD). DHA in plasma is normally positively associated with DHA intake. However, despite being associated with lower fish and DHA intake, unexpectedly, plasma (or brain) DHA is frequently not lower in AD. This review will highlight some metabolic and physiological factors such as ageing and apoE polymorphism that influence DHA homeostasis. Compared with young adults, blood DHA is often slightly but significantly higher in older adults without any age-related cognitive decline. Higher plasma DHA in older adults could be a sign that their fish or DHA intake is higher. However, our supplementation and carbon-13 tracer studies also show that DHA metabolism, e.g. transit through the plasma, apparent retroconversion and β-oxidation, is altered in healthy older compared with healthy young adults. ApoE4 increases the risk of AD, possibly in part because it too changes DHA homeostasis. Therefore, independent of differences in fish intake, changing DHA homeostasis may tend to obscure the relationship between DHA intake and plasma DHA which, in turn, may contribute to making older adults more susceptible to cognitive decline despite older adults having similar or sometimes higher plasma DHA than in younger adults. In conclusion, recent development of new tools such as isotopically labelled DHA to study DHA metabolism in human subjects highlights some promising avenues to evaluate how and why DHA metabolism changes during ageing and AD.
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Ammann EM, Pottala JV, Harris WS, Espeland MA, Wallace R, Denburg NL, Carnahan RM, Robinson JG. ω-3 fatty acids and domain-specific cognitive aging: secondary analyses of data from WHISCA. Neurology 2013; 81:1484-91. [PMID: 24068783 DOI: 10.1212/wnl.0b013e3182a9584c] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To test the hypothesis that higher levels of red blood cell (RBC) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have a protective association with domain-specific cognitive function in women aged 65 years and older. METHODS A total of 2,157 women with normal cognition enrolled in a clinical trial of postmenopausal hormone therapy were followed with annual cognitive testing for a median of 5.9 years. In this retrospective cohort study, we assessed the relationship between prerandomization RBC DHA + EPA levels and a) cognitive measures at baseline, and b) cognitive change over time. Endpoints were composite cognitive function and performance in 7 cognitive domains: fine motor speed, verbal memory, visual memory, spatial ability, verbal knowledge, verbal fluency, and working memory. RESULTS After adjustment for demographic, clinical, and behavioral characteristics, no significant (p < 0.01) cross-sectional cognitive differences were found between women in the high and low DHA + EPA tertiles at the time of the first annual cognitive battery. In addition, no significant (p < 0.01) differences were found between the high and low DHA + EPA tertiles in the rate of cognitive change over time. CONCLUSIONS We did not find an association between RBC DHA + EPA levels and age-associated cognitive decline in a cohort of older, dementia-free women.
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Affiliation(s)
- Eric M Ammann
- From the Department of Epidemiology (E.M.A., R.W., R.M.C., J.G.R.), College of Public Health, and Departments of Internal Medicine (R.W., J.G.R.) and Neurology (N.L.D.), College of Medicine, University of Iowa, Iowa City; OmegaQuant Analytics (J.V.P., W.S.H.), Sioux Falls; Department of Medicine (W.S.H.), Sanford School of Medicine, University of South Dakota, Vermillion; and Department of Biostatistical Sciences (M.A.E.), Wake Forest School of Medicine, Winston-Salem, NC
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