Squitti Rosanna, Simonelli Ilaria, Cassetta Emanuele, Lupoi Domenico, Rongioletti Mauro, Ventriglia Mariacarla, Siotto Mariacristina
Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio- Fatebenefratelli, 25125 Brescia. Italy.
Fatebenefratelli Foundation, AFaR Division, Fatebenefratelli Hospital, Isola Tiberina, Rome. Italy.
Curr Alzheimer Res. 2017;14(12):1318-1326. doi: 10.2174/1567205014666170623125156.
Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in serum is higher in a percentage of Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype.
In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off.
We assessed levels of copper, ceruloplasmin, non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and β-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in 'Normal' and 'High' non-Cp Cu groups.
The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parietooccipital and temporal white matter hyperintensities), infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042).
This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; non-Cp Cu appears a good marker of this copper AD.
荟萃分析表明，阿尔茨海默病（AD）患者血清中未与铜蓝蛋白结合的铜（非铜蓝蛋白结合铜，也称为“游离”铜）比例更高。基于非铜蓝蛋白结合铜临界值分层的AD患者的遗传异质性支持了铜代谢异常的AD亚型的存在。
为了找到与铜异常相关的可检测的AD代谢亚型存在的证据，我们探讨了在基于非铜蓝蛋白结合铜临界值对患者进行分层而分为两组的同质且特征明确的AD人群中，神经影像模式异质性的假设。
我们评估了66例AD患者的铜、铜蓝蛋白、非铜蓝蛋白结合铜、脑脊液中总Tau蛋白（h-tau）、苏氨酸181磷酸化Tau蛋白（P-tau）和β-淀粉样蛋白1-42水平以及APOE4基因型，并比较了分为“正常”和“高”非铜蓝蛋白结合铜组的AD患者脑萎缩视觉评分量表和神经血管负担的神经影像指标。
基于非铜蓝蛋白结合铜分层产生的AD组在内侧颞叶萎缩、脑室周围高信号、深部高信号（包括额叶、顶枕叶和颞叶白质高信号）、幕下高信号指数方面无差异，但在整体萎缩方面存在差异。更具体地说，高非铜蓝蛋白结合铜组中的AD患者整体萎缩负担较轻（p=0.042）。
AD组之间的这种神经影像异质性提示存在AD的铜代谢亚型；非铜蓝蛋白结合铜似乎是这种铜代谢异常的AD的良好标志物。
