Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance : A nontargeted metabolomic study. / Snowden, Stuart; Ebshiana, Amera; Hye, Abdul; An, Yang ; Pletnikova, Olga; O'Brien, Richard ; Troncoso, John; Legido-Quigley, Cristina; Thambisetty, Madhav.

In: PLOS medicine, Vol. 14, No. 3, e1002266, 21.03.2017, p. 1-19.

Research output: Contribution to journalArticlepeer-review

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Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance : A nontargeted metabolomic study. / Snowden, Stuart; Ebshiana, Amera; Hye, Abdul; An, Yang ; Pletnikova, Olga; O'Brien, Richard ; Troncoso, John; Legido-Quigley, Cristina; Thambisetty, Madhav.

In: PLOS medicine, Vol. 14, No. 3, e1002266, 21.03.2017, p. 1-19.

Research output: Contribution to journalArticlepeer-review

Harvard

Snowden, S, Ebshiana, A, Hye, A, An, Y, Pletnikova, O, O'Brien, R, Troncoso, J, Legido-Quigley, C & Thambisetty, M 2017, 'Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study', PLOS medicine, vol. 14, no. 3, e1002266, pp. 1-19. https://doi.org/10.1371/journal.pmed.1002266

APA

Snowden, S., Ebshiana, A., Hye, A., An, Y., Pletnikova, O., O'Brien, R., Troncoso, J., Legido-Quigley, C., & Thambisetty, M. (2017). Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study. PLOS medicine, 14(3), 1-19. [e1002266]. https://doi.org/10.1371/journal.pmed.1002266

Vancouver

Author

Snowden, Stuart ; Ebshiana, Amera ; Hye, Abdul ; An, Yang ; Pletnikova, Olga ; O'Brien, Richard ; Troncoso, John ; Legido-Quigley, Cristina ; Thambisetty, Madhav. / Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance : A nontargeted metabolomic study. In: PLOS medicine. 2017 ; Vol. 14, No. 3. pp. 1-19.

BibTeX

@article{72422c595641448a9cf105d54458278f,
title = "Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance: A nontargeted metabolomic study",
abstract = "Background  The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain. Methods and findings  We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and “asymptomatic Alzheimer{\textquoteright}s disease” (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10−8, FC = 0.52, q = 1.03 x 10−6), linolenic acid (p = 2.5 x 10−4, FC = 0.84, q = 4.03 x 10−4), docosahexaenoic acid (p = 1.7 x 10−7, FC = 1.45, q = 1.24 x 10−6), eicosapentaenoic acid (p = 4.4 x 10−4, FC = 0.16, q = 6.48 x 10−4), oleic acid (p = 3.3 x 10−7, FC = 0.34, q = 1.46 x 10−6), and arachidonic acid (p = 2.98 x 10−5, FC = 0.75, q = 7.95 x 10−5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.Conclusions  The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.",
author = "Stuart Snowden and Amera Ebshiana and Abdul Hye and Yang An and Olga Pletnikova and Richard O'Brien and John Troncoso and Cristina Legido-Quigley and Madhav Thambisetty",
year = "2017",
month = mar,
day = "21",
doi = "10.1371/journal.pmed.1002266",
language = "English",
volume = "14",
pages = "1--19",
journal = "PLOS medicine",
issn = "1549-1277",
publisher = "Public Library of Science",
number = "3",

}

RIS

TY - JOUR

T1 - Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance

T2 - A nontargeted metabolomic study

AU - Snowden, Stuart

AU - Ebshiana, Amera

AU - Hye, Abdul

AU - An, Yang

AU - Pletnikova, Olga

AU - O'Brien, Richard

AU - Troncoso, John

AU - Legido-Quigley, Cristina

AU - Thambisetty, Madhav

PY - 2017/3/21

Y1 - 2017/3/21

N2 - Background  The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain. Methods and findings  We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and “asymptomatic Alzheimer’s disease” (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10−8, FC = 0.52, q = 1.03 x 10−6), linolenic acid (p = 2.5 x 10−4, FC = 0.84, q = 4.03 x 10−4), docosahexaenoic acid (p = 1.7 x 10−7, FC = 1.45, q = 1.24 x 10−6), eicosapentaenoic acid (p = 4.4 x 10−4, FC = 0.16, q = 6.48 x 10−4), oleic acid (p = 3.3 x 10−7, FC = 0.34, q = 1.46 x 10−6), and arachidonic acid (p = 2.98 x 10−5, FC = 0.75, q = 7.95 x 10−5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.Conclusions  The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

AB - Background  The metabolic basis of Alzheimer disease (AD) pathology and expression of AD symptoms is poorly understood. Omega-3 and -6 fatty acids have previously been linked to both protective and pathogenic effects in AD. However, to date little is known about how the abundance of these species is affected by differing levels of disease pathology in the brain. Methods and findings  We performed metabolic profiling on brain tissue samples from 43 individuals ranging in age from 57 to 95 y old who were stratified into three groups: AD (N = 14), controls (N = 14) and “asymptomatic Alzheimer’s disease” (ASYMAD), i.e., individuals with significant AD neuropathology at death but without evidence for cognitive impairment during life (N = 15) from the autopsy sample of the Baltimore Longitudinal Study of Aging (BLSA). We measured 4,897 metabolite features in regions both vulnerable in the middle frontal and inferior temporal gyri (MFG and ITG) and resistant (cerebellum) to classical AD pathology. The levels of six unsaturated fatty acids (UFAs) in whole brain were compared in controls versus AD, and the differences were as follows: linoleic acid (p = 8.8 x 10−8, FC = 0.52, q = 1.03 x 10−6), linolenic acid (p = 2.5 x 10−4, FC = 0.84, q = 4.03 x 10−4), docosahexaenoic acid (p = 1.7 x 10−7, FC = 1.45, q = 1.24 x 10−6), eicosapentaenoic acid (p = 4.4 x 10−4, FC = 0.16, q = 6.48 x 10−4), oleic acid (p = 3.3 x 10−7, FC = 0.34, q = 1.46 x 10−6), and arachidonic acid (p = 2.98 x 10−5, FC = 0.75, q = 7.95 x 10−5). These fatty acids were strongly associated with AD when comparing the groups in the MFG and ITG, respectively: linoleic acid (p < 0.0001, p = 0.0006), linolenic acid (p < 0.0001, p = 0.002), docosahexaenoic acid (p < 0.0001, p = 0.0024), eicosapentaenoic acid (p = 0.0002, p = 0.0008), oleic acid (p < 0.0001, p = 0.0003), and arachidonic acid (p = 0.0001, p = 0.001). Significant associations were also observed between the abundance of these UFAs with neuritic plaque and neurofibrillary tangle burden as well as domain-specific cognitive performance assessed during life. Based on the regional pattern of differences in brain tissue levels of these metabolites, we propose that alterations in UFA metabolism represent both global metabolic perturbations in AD as well as those related to specific features of AD pathology. Within the middle frontal gyrus, decrements in linoleic acid, linolenic acid, and arachidonic acid (control>ASYMAD>AD) and increases in docosahexanoic acid (AD>ASYMAD>control) may represent regionally specific threshold levels of these metabolites beyond which the accumulation of AD pathology triggers the expression of clinical symptoms. The main limitation of this study is the relatively small sample size. There are few cohorts with extensive longitudinal cognitive assessments during life and detailed neuropathological assessments at death, such as the BLSA.Conclusions  The findings of this study suggest that unsaturated fatty acid metabolism is significantly dysregulated in the brains of patients with varying degrees of Alzheimer pathology.

U2 - 10.1371/journal.pmed.1002266

DO - 10.1371/journal.pmed.1002266

M3 - Article

VL - 14

SP - 1

EP - 19

JO - PLOS medicine

JF - PLOS medicine

SN - 1549-1277

IS - 3

M1 - e1002266

ER -