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Cited by 79Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMemory and Neural Mechanisms

Contributions of a high-fat diet to Alzheimer’s disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models

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Rollins, Colleen P.E., Gallino, Daniel, Kong, Vincent, Ayranci, Gülebru, Devenyi, Gabriel A., Germann, Jürgen, Chakravarty, M. Mallar·2019·NeuroImage: Clinical
DOI 10.1016/j.nicl.2018.11.016PMC PMC6413478
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Abstract

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported that obesity accelerates AD-related pathophysiology and memory impairment in mouse models of AD. However, the nature of the brain structure-behaviour relationship mediating this acceleration remains unclear. In this manuscript we evaluated the impact of adolescent obesity on the brain morphology of the triple transgenic mouse model of AD (3xTg) and a non-transgenic control model of the same background strain (B6129s) using longitudinally acquired structural magnetic resonance imaging (MRI). At 8 weeks of age, animals were placed on a high-fat diet (HFD) or an ingredient-equivalent control diet (CD). Structural images were acquired at 8, 16, and 24 weeks. At 25 weeks, animals underwent the novel object recognition (NOR) task and the Morris water maze (MWM) to assess short-term non-associative memory and spatial memory, respectively. All analyses were carried out across four groups: B6129s-CD and -HFD and 3xTg-CD and -HFD. Neuroanatomical changes in MRI-derived brain morphology were assessed using volumetric and deformation-based analyses. HFD-induced obesity during adolescence exacerbated brain volume alterations by adult life in the 3xTg mouse model in comparison to control-fed mice and mediated volumetric alterations of select brain regions, such as the hippocampus. Further, HFD-induced obesity aggravated memory in all mice, lowering certain memory measures of B6129s control mice to the level of 3xTg mice maintained on a CD. Moreover, decline in the volumetric trajectories of hippocampal regions for all mice were associated with the degree of spatial memory impairments on the MWM. Our results suggest that obesity may interact with the brain changes associated with AD-related pathology in the 3xTg mouse model to aggravate brain atrophy and memory impairments and similarly impair brain structural integrity and memory capacity of non-transgenic mice. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

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  • Longitudinal studies have revealed significant changes in brain volumes (both increases and decreases) in 3×Tg-AD mice during the early stages from 1.5 months to 6 months of age.

    “Longitudinal studies have revealed significant changes in brain volumes (both increases and decreases) in 3×Tg-AD mice during the early stages from 1.5 months to 6 months of age (Kong et al., 2018; Rollins et al., 2019).”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Rollins et al., 2019

    The Results (Fig. 5) report significant increases and decreases in local brain volume in 3xTg-AD mice over time. However, Magnetic resonance image acquisition specifies measurements at 8, 16, and 24 weeks of age—approximately 2 to 6 months—not from 1.5 months. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Sample sizes were not predetermined using statistical methods, but were similar to those reported in previous publications.

    “Sample sizes were not predetermined using statistical methods; however, our sample sizes are similar to those reported in previous publications (Manno et al., 2019; Rollins et al., 2019; Güell-Bosch et al., 2020).”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Rollins et al., 2019

  • Brain-wide volume measurements have yielded inconsistent results in the 3×Tg-AD model, with some studies reporting volumetric changes and others finding no significant differences.

    “Although most studies have reported volumetric changes throughout various brain regions over time (including both decreases and increases) (Kong et al., 2018; Chiquita et al., 2019; Rollins et al., 2019; Güell-Bosch et al., 2020), others have found no significant differences in brain volume between 3×Tg-AD mice and controls (Kastyak-Ibrahim et al., 2013; Wu et al., 2015; Montoliu-Gaya et al., 2018”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Rollins et al., 2019

  • A previous study in a mouse model of AD reported lower volumes in the right stria terminalis at 6 months of age.

    “A previous study in a mouse model of AD reported lower volumes in the right stria terminalis at 6 months of age (Rollins et al., 2019).”

    From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Rollins et al., 2019

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References 83 · Cited by 79

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  1. Alford S. Patel D. Perakakis N. Mantzoros C.S. Obesity as a risk factor for Alzheimer's disease: weighing the evidence Obes Rev 2017 29024348
  2. Allemang-Grand R. Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes Mol Autism 8 2017 32 28670438 PMC5485541
  3. Amaral R.S. Manual segmentation of the fornix, fimbria, and alveus on high-resolution 3T MRI: Application via fully-automated mapping of the human memory circuit white and grey matter in healthy and pathological aging NeuroImage 2016 27765611
  4. Avants B.B. Epstein C.L. Grossman M. Gee J.C. Symmetric diffeomorphic image registration with cross-correlation: evaluating automated labeling of elderly and neurodegenerative brain Med. Image Anal. 12 2008 26 41 17659998 PMC2276735
  5. Avants B.B. A reproducible evaluation of ANTs similarity metric performance in brain image registration NeuroImage 54 2011 2033 2044 20851191 PMC3065962
  6. Barnes D.E. Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence Lancet Neurol. 10 2011 819 828 21775213 PMC3647614
  7. Barron A.M. Rosario E.R. Elteriefi R. Pike C.J. Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer's disease PLoS One 8 2013 e78554 PMC3810257 24205258
  8. Biro F.M. Wien M. Childhood obesity and adult morbidities Am. J. Clin. Nutr. 91 2010 1499S 1505S 20335542 PMC2854915
  9. Bischof G.N. Park D.C. Obesity and Aging: Consequences for Cognition, Brain Structure, and Brain Function Psychosom Med 77 2015 697 709 26107577 PMC5648343
  10. Bobb J.F. Schwartz B.S. Davatzikos C. Caffo B. Cross-sectional and longitudinal association of body mass index and brain volume Hum. Brain Mapp. 35 2014 75 88 23008165 PMC3615109
  11. Boitard C. Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice Hippocampus 22 2012 2095 2100 22593080
  12. Boitard C. Switching Adolescent High-Fat Diet to Adult Control Diet Restores Neurocognitive Alterations Front. Behav. Neurosci. 10 2016 225 27917115 PMC5116459
  13. Chakravarty M.M. Performing label-fusion-based segmentation using multiple automatically generated templates Hum. Brain Mapp. 34 2013 2635 2654 22611030 PMC4896505
  14. Chakravarty M.M. Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature NeuroImage 125 2016 422 427 26525655
  15. Chung M.K. A unified statistical approach to deformation-based morphometry NeuroImage 14 2001 595 606 11506533
  16. de Flores R. La Joie R. Chetelat G. Structural imaging of hippocampal subfields in healthy aging and Alzheimer's disease Neuroscience 309 2015 29 50 26306871
  17. Dorr A.E. Lerch J.P. Spring S. Kabani N. Henkelman R.M. High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice NeuroImage 42 2008 60 69 18502665
  18. Eriksen J.L. Janus C.G. Plaques, tangles, and memory loss in mouse models of neurodegeneration Behav. Genet. 37 2007 79 100 17072762
  19. Freeman L.R. Haley-Zitlin V. Rosenberger D.S. Granholm A.C. Damaging effects of a high-fat diet to the brain and cognition: a review of proposed mechanisms Nutr Neurosci 17 2014 241 251 24192577 PMC4074256
  20. Friedel M. van Eede M.C. Pipitone J. Chakravarty M.M. Lerch J.P. Pydpiper: a flexible toolkit for constructing novel registration pipelines Front Neuroinform 8 2014 67 25126069 PMC4115634
  21. Gratuze M. High-fat, high-sugar, and high-cholesterol consumption does not impact tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology Neurobiol. Aging 47 2016 71 73 27565300
  22. Guma E. Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor NeuroImage 176 2018 226 238 29704613
  23. Guyenet S.J. Schwartz M.W. Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity J. Clin. Endocrinol. Metab. 97 2012 745 755 22238401 PMC3319208
  24. Heyward F.D. Adult mice maintained on a high-fat diet exhibit object location memory deficits and reduced hippocampal SIRT1 gene expression Neurobiol. Learn. Mem. 98 2012 25 32 22542746 PMC3389577
  25. Ho A.J. Obesity is linked with lower brain volume in 700 AD and MCI patients Neurobiol. Aging 31 2010 1326 1339 20570405 PMC3197833
  26. Ho A.J. Hippocampal volume is related to body mass index in Alzheimer's disease Neuroreport 22 2011 10 14 21539003 PMC3197837
  27. Hueston C.M. Cryan J.F. Nolan Y.M. Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators Transl. Psychiatry 7 2017 e1081 PMC5416690 28375209
  28. Julien C. High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model Neurobiol. Aging 31 2010 1516 1531 18926603
  29. Kang S. Lee Y.H. Lee J.E. Metabolism-Centric Overview of the Pathogenesis of Alzheimer's Disease Yonsei Med. J. 58 2017 479 488 28332351 PMC5368131
  30. Kim T.W. Choi H.H. Chung Y.R. Treadmill exercise alleviates impairment of cognitive function by enhancing hippocampal neuroplasticity in the high-fat diet-induced obese mice J Exerc Rehabil 12 2016 156 162 27419109 PMC4934958
  31. Kivipelto M. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study Lancet Neurol. 5 2006 735 741 16914401
  32. Kong V. Early-in-life neuroanatomical and behavioural trajectories in a triple transgenic model of Alzheimer's disease Brain Struct Funct 2018 29948190
  33. Kuo Y.T. Herlihy A.H. So P.W. Bhakoo K.K. Bell J.D. In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride J. Magn. Reson. Imaging 21 2005 334 339 15779025
  34. Lau J.C. Longitudinal neuroanatomical changes determined by deformation-based morphometry in a mouse model of Alzheimer's disease NeuroImage 42 2008 19 27 18547819
  35. Lee J.H. Silva A.C. Merkle H. Koretsky A.P. Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: dose-dependent and temporal evolution of T1 contrast Magn. Reson. Med. 53 2005 640 648 15723400
  36. Livingston G. Dementia prevention, intervention, and care Lancet 2017 28735855
  37. Luciano R. Biomarkers of Alzheimer disease, insulin resistance, and obesity in childhood Pediatrics 135 2015 1074 1081 25963004
  38. Malheiros J.M. Paiva F.F. Longo B.M. Hamani C. Covolan L. Manganese-Enhanced MRI: Biological applications in Neuroscience Front. Neurol. 6 2015 161 26217304 PMC4498388
  39. Manjon J.V. Tohka J. Robles M. Improved estimates of partial volume coefficients from noisy brain MRI using spatial context NeuroImage 53 2010 480 490 20600978
  40. Martin S.A. Jameson C.H. Allan S.M. Lawrence C.B. Maternal high-fat diet worsens memory deficits in the triple-transgenic (3xTgAD) mouse model of Alzheimer's disease PloS One 9 6 2014 PMC4053375 24918775
  41. Massaad C.A. Pautler R.G. Manganese-enhanced magnetic resonance imaging (MEMRI) Methods Mol. Biol. 711 2011 145 174 21279601 PMC3285478
  42. Mastrangelo M.A. Bowers W.J. Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice BMC Neurosci. 9 2008 81 18700006 PMC2527610
  43. Moceri V.M. Kukull W.A. Emanuel I. van Belle G. Larson E.B. Early-life risk factors and the development of Alzheimer's disease Neurology 54 2000 415 420 10668705
  44. Ng M. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013 Lancet 384 2014 766 781 24880830 PMC4624264
  45. Oddo S. Caccamo A. Kitazawa M. Tseng B.P. Laferla F.M. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease Neurobiol. Aging 24 2003 1063 1070 14643377
  46. Oddo S. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction Neuron 39 2003 409 421 12895417
  47. Poole D.S. Continuous infusion of manganese improves contrast and reduces side effects in manganese-enhanced magnetic resonance imaging studies NeuroImage 147 2017 1 9 27777173
  48. Reichelt A.C. Adolescent Maturational Transitions in the Prefrontal Cortex and Dopamine Signaling as a risk factor for the Development of Obesity and High Fat/High Sugar Diet Induced Cognitive Deficits Front. Behav. Neurosci. 10 2016 189 27790098 PMC5061823
  49. Reinert K.R. Po'e E.K. Barkin S.L. The relationship between executive function and obesity in children and adolescents: a systematic literature review Journal of obesity 2013 2013 820956 23533726 PMC3595670
  50. Ronan L. Obesity associated with increased brain age from midlife Neurobiol. Aging 47 2016 63 70 27562529 PMC5082766
  51. Sawyer S.M. Adolescence: a foundation for future health Lancet 379 2012 1630 1640 22538178
  52. Schneider L.S. Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 2014 J. Intern. Med. 275 2014 251 283 24605808 PMC3956752
  53. Seifan A. Schelke M. Obeng-Aduasare Y. Isaacson R. Early Life Epidemiology of Alzheimer's Disease--a critical Review Neuroepidemiology 45 2015 237 254 26501691 PMC4679687
  54. Seo Y. Mn-bicine: a low affinity chelate for manganese ion enhanced MRI Magn. Reson. Med. 65 2011 1005 1012 21413064
  55. Shaw P. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study Lancet Neurol. 6 2007 494 500 17509484
  56. Silva A.C. Bock N.A. Manganese-enhanced MRI: an exceptional tool in translational neuroimaging Schizophr. Bull. 34 2008 595 604 18550591 PMC2632451
  57. Simmonds M. Llewellyn A. Owen C.G. Woolacott N. Predicting adult obesity from childhood obesity: a systematic review and meta-analysis Obes. Rev. 17 2016 95 107 26696565
  58. Steadman P.E. Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas Autism Res. 7 2014 124 137 24151012 PMC4418792
  59. Tardif C.L. Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease Hum. Brain Mapp. 39 2018 971 984 29164798 PMC6866392
  60. The N.S. Suchindran C. North K.E. Popkin B.M. Gordon-Larsen P. Association of adolescent obesity with risk of severe obesity in adulthood JAMA 304 2010 2042 2047 21063014 PMC3076068
  61. Ullmann J.F. An MRI atlas of the mouse basal ganglia Brain Struct. Funct. 219 2014 1343 1353 23689500
  62. Valladolid-Acebes I. High-fat diets impair spatial learning in the radial-arm maze in mice Neurobiol. Learn. Mem. 95 2011 80 85 21093599
  63. Vandal M. Insulin reverses the high-fat diet-induced increase in brain Abeta and improves memory in an animal model of Alzheimer disease Diabetes 63 2014 4291 4301 25008180
  64. Voineskos A.N. Hippocampal (subfield) volume and shape in relation to cognitive performance across the adult lifespan Hum. Brain Mapp. 36 2015 3020 3037 25959503 PMC6869683
  65. Voss M.W. Vivar C. Kramer A.F. van Praag H. Bridging animal and human models of exercise-induced brain plasticity Trends Cogn. Sci. 17 2013 525 544 24029446 PMC4565723
  66. Vousden D.A. Continuous manganese delivery via osmotic pumps for manganese-enhanced mouse MRI does not impair spatial learning but leads to skin ulceration NeuroImage 173 2018 411 420 29505831
  67. Walker J.M. Dixit S. Saulsberry A.C. May J.M. Harrison F.E. Reversal of high fat diet-induced obesity improves glucose tolerance, inflammatory response, beta-amyloid accumulation and cognitive decline in the APP/PSEN1 mouse model of Alzheimer's disease Neurobiol. Dis. 100 2017 87 98 28108292 PMC5316363
  68. Whitmer R.A. Central obesity and increased risk of dementia more than three decades later Neurology 71 2008 1057 1064 18367704
  69. Xu W.L. Midlife overweight and obesity increase late-life dementia risk: a population-based twin study Neurology 76 2011 1568 1574 21536637 PMC3100125
  70. Yau P.L. Castro M.G. Tagani A. Tsui W.H. Convit A. Obesity and metabolic syndrome and functional and structural brain impairments in adolescence Pediatrics 130 2012 e856 e864 22945407 PMC3457620
  71. Zanchi D. Giannakopoulos P. Borgwardt S. Rodriguez C. Haller S. Hippocampal and Amygdala Gray Matter loss in elderly Controls with Subtle Cognitive Decline Front. Aging Neurosci. 9 2017 50 28326035 PMC5340094
  72. Zhang J. Longitudinal characterization of brain atrophy of a Huntington's disease mouse model by automated morphological analyses of magnetic resonance images NeuroImage 49 2010 2340 2351 19850133 PMC2929697
  73. Ziegler G. Dahnke R. Gaser C. Alzheimer's Disease Neuroimaging, I. Models of the aging brain structure and individual decline Front Neuroinform 6 3 2012 PMC3303090 22435060

Authors
Rollins, C. P. E., Gallino, D., Kong, V., Ayranci, G., Devenyi, G. A., Germann, J., & Chakravarty, M. M.
Affiliations
  • University of Cambridge (GB)
  • Douglas Mental Health University Institute (CA)
Corresponding author
  • Rollins, Colleen P.E.
  • Chakravarty, M. Mallar
ORCID
Venue
NeuroImage: Clinical
Publisher
Elsevier BV
Published
2019
Volume
21
Pages
101606
ISSN
2213-1582 (ISSN-L)
DOI
10.1016/j.nicl.2018.11.016
PMC
PMC6413478
OpenAlex
W2901046251
Cited by
79
References
83
Citations by year
2026: 9 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 15 · 2021: 9 · 2020: 7 · 2019: 9
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • NeuroImage Clinical (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fonds de Recherche du Québec - Santé
  • Fondation Brain Canada
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, high-fat diet, adolescent obesity, triple transgenic mouse model, hippocampal atrophy, brain volume changes, spatial memory impairment, novel object recognition, memory decline, obesity as risk factor, lifestyle intervention
MeSH terms
Alzheimer Disease, Animals, Behavior, Animal, Brain, Disease Models, Animal, Female, Magnetic Resonance Imaging, Male, Memory Disorders, Memory, Short-Term, Amyloid beta-Protein Precursor, tau Proteins, Mice, Diet, High-Fat, Neuroimaging, Cognitive Dysfunction, Spatial Memory

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