肌醇变化先于淀粉样蛋白病理改变，且与阿尔茨海默病中的APOE基因型相关。
Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease.
作者信息
Voevodskaya Olga, Sundgren Pia C, Strandberg Olof, Zetterberg Henrik, Minthon Lennart, Blennow Kaj, Wahlund Lars-Olof, Westman Eric, Hansson Oskar
机构信息
From Clinical Geriatrics (O.V., L.-O.W., E.W.), Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm; Department of Diagnostic Radiology (P.C.S., O.S.), Lund University; Clinical Neurochemistry Laboratory (H.Z., K.B.), Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology (H.Z.), Queen Square, London, UK; Memory Clinic (L.M., O.H.), Skåne University Hospital; and Clinical Memory Research Unit (L.M., O.H.), Department of Clinical Sciences, Malmö, Lund University, Sweden.
出版信息
Neurology. 2016 May 10;86(19):1754-61. doi: 10.1212/WNL.0000000000002672. Epub 2016 Apr 15.
OBJECTIVE
We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity.
METHODS
In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE.
RESULTS
Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology.
CONCLUSIONS
mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology.
目的
我们旨在测试磁共振波谱（MRS）代谢物肌醇（mI）、N - 乙酰天门冬氨酸（NAA）和胆碱的体内水平在临床前阿尔茨海默病（AD）期间是否已经异常，并将这些变化与淀粉样蛋白或tau病理以及功能连接性相关联。
方法
在这项横断面多中心研究（前瞻性瑞典生物标志物研究的一个子集）中，我们纳入了4组，代表了痴呆前AD的不同阶段：（1）脑脊液β - 淀粉样蛋白42（Aβ42）正常的认知健康老年人，（2）脑脊液Aβ42异常的认知健康老年人，（3）主观认知下降且脑脊液Aβ42异常的患者，（4）轻度认知下降且脑脊液Aβ42异常的患者（N总计 = 352）。在后扣带回/楔前叶测量的光谱标志物与已知的疾病生物标志物一起被考虑：脑脊液Aβ42、磷酸化tau、总tau、[（18）F] - 氟代脱氧葡萄糖正电子发射断层扫描（PET）、功能磁共振成像（f - MRI）以及遗传风险因素载脂蛋白E（APOE）。
结果
与淀粉样蛋白阴性的健康老年人相比，淀粉样蛋白阳性的认知健康参与者的mI/肌酸和mI/NAA水平显著升高（p < 0.05）。在淀粉样蛋白阳性的健康老年人中，mI/肌酸和mI/NAA与[（18）F]氟代脱氧葡萄糖示踪剂在皮质的滞留相关（分别为[公式：见原文] = 0.44，p = 0.02和[公式：见原文] = 0.51，p = 0.01）。脑脊液Aβ42水平正常的健康APOE ε4携带者的mI/肌酸水平显著高于ε4非携带者（p < 0.001）。最后，mI/肌酸升高与默认模式网络内的功能连接性降低相关（皮尔逊相关系数r = -0.16，p = 0.02），独立于淀粉样蛋白病理。
结论
mI水平在AD的无症状阶段就已升高。此外，脑脊液Aβ42水平正常的健康APOE ε4携带者的mI/肌酸浓度升高，表明mI水平可能在可检测到淀粉样蛋白病理之前揭示APOE ε4对区域脑的影响。
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