Snowden Stuart G, Ebshiana Amera A, Hye Abdul, An Yang, Pletnikova Olga, O'Brien Richard, Troncoso John, Legido-Quigley Cristina, Thambisetty Madhav
Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
PLoS Med. 2017 Mar 21;14(3):e1002266. doi: 10.1371/journal.pmed.1002266. eCollection 2017 Mar.
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.
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.
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.
阿尔茨海默病（AD）病理的代谢基础以及AD症状的表现目前仍知之甚少。此前，ω-3和ω-6脂肪酸与AD的保护作用和致病作用均有关联。然而，迄今为止，对于大脑中不同疾病病理水平如何影响这些脂肪酸的丰度，人们了解甚少。
我们对43名年龄在57至95岁之间的个体的脑组织样本进行了代谢谱分析，这些个体被分为三组：AD组（N = 14）、对照组（N = 14）和“无症状阿尔茨海默病”（ASYMAD）组，即死亡时具有显著AD神经病理学特征但生前无认知障碍证据的个体（N = 15），样本来自巴尔的摩纵向衰老研究（BLSA）的尸检样本。我们在中额叶和颞下回（MFG和ITG）易损区域以及对经典AD病理具有抗性的区域（小脑）测量了4897种代谢物特征。比较了对照组与AD组全脑中六种不饱和脂肪酸（UFA）的水平，差异如下：亚油酸（p = 8.8×10⁻⁸，FC = 0.52，q = 1.03×10⁻⁶）、亚麻酸（p = 2.5×10⁻⁴，FC = 0.84，q = 4.03×10⁻⁴）、二十二碳六烯酸（p = 1.7×10⁻⁷，FC = 1.45，q = 1.24×10⁻⁶）、二十碳五烯酸（p = 4.4×10⁻⁴，FC = 0.16，q = 6.48×10⁻⁴）、油酸（p = 3.3×10⁻⁷，FC = 0.34，q = 1.46×10⁻⁶）和花生四烯酸（p = 2.98×10⁻⁵，FC = 0.75，q = 7.95×10⁻⁵）。当分别比较MFG和ITG组中的这些脂肪酸时，它们与AD密切相关：亚油酸（p < 0.0001，p = 0.0006）、亚麻酸（p < 0.0001，p = 0.002）、二十二碳六烯酸（p < 0.0001，p = 0.0024）、二十碳五烯酸（p = 0.0002，p = 0.0008）、油酸（p < 0.0001，p = 0.0003）和花生四烯酸（p = 0.0001，p = 0.001）。还观察到这些UFA的丰度与神经炎性斑块和神经原纤维缠结负担以及生前评估的特定领域认知表现之间存在显著关联。基于这些代谢物在脑组织水平上的区域差异模式，我们提出UFA代谢的改变既代表了AD中的整体代谢紊乱，也代表了与AD病理特定特征相关的代谢紊乱。在中额叶回内，亚油酸、亚麻酸和花生四烯酸的减少（对照组＞ASYMAD组＞AD组）以及二十二碳六烯酸的增加（AD组＞ASYMAD组＞对照组）可能代表了这些代谢物的区域特异性阈值水平，超过该阈值，AD病理的积累会触发临床症状的表达。本研究的主要局限性是样本量相对较小。很少有队列在生前进行广泛的纵向认知评估，并在死亡时进行详细的神经病理学评估，如BLSA。
本研究结果表明，在不同程度阿尔茨海默病病理的患者大脑中，不饱和脂肪酸代谢存在显著失调。
