PDF(Pubmed)
Abstract：
Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer\'s disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s).
In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.
The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.
We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.
In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD.
The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss.
We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline.
摘要：
tau的过度磷酸化导致构象变化，使微管不稳定并阻碍阿尔茨海默病（AD）中的轴突运输。然而,尚不清楚AD引起的白质（WM）下降是否与特定的Tau磷酸化位点有关。
在常染色体显性遗传AD（ADAD）突变携带者（MC）和非携带者（NC）中，我们比较了脑脊液（CSF）在tau位点（pT217，pT181，pS202和pT205）和总tau与WM测量的磷酸化，从扩散张量成像(DTI)导出，和认知。WM复合度量，由主成分分析得出，用于识别ADAD中的空间下降。
WM复合解释了超过70%的MC方差。对空间地形有重要贡献的WM区域位于call骨和扣带区域。WM复合材料中完整性的丧失与MC中的AD进展密切相关，如估计的发病年限（EYO）和认知能力下降所定义的。线性回归表明淀粉样蛋白，CSFtau位点pT205的灰质萎缩和磷酸化各自独特地解释了MC内WM复合物的减少，这与血管变化（白质高强度）无关，和年龄。CSFtau在其他位点的过度磷酸化和总tau并未显着预测WM复合损失。
我们确定了CSF磷酸化tau与MC内WM下降之间的位点特异性关系。pT205处淀粉样蛋白沉积和Tau磷酸化的存在与WM复合物损失有关。这些发现强调了WM功能障碍的主要AD特异性机制，该机制与症状表现和认知能力下降密切相关。
在常染色体显性遗传AD（ADAD）突变携带者（MC）和非携带者（NC）中，我们比较了脑脊液（CSF）在tau位点（pT217，pT181，pS202和pT205）和总tau与WM测量的磷酸化，从扩散张量成像(DTI)导出，和认知。WM复合度量，由主成分分析得出，用于识别ADAD中的空间下降。
WM复合解释了超过70%的MC方差。对空间地形有重要贡献的WM区域位于call骨和扣带区域。WM复合材料中完整性的丧失与MC中的AD进展密切相关，如估计的发病年限（EYO）和认知能力下降所定义的。线性回归表明淀粉样蛋白，CSFtau位点pT205的灰质萎缩和磷酸化各自独特地解释了MC内WM复合物的减少，这与血管变化（白质高强度）无关，和年龄。CSFtau在其他位点的过度磷酸化和总tau并未显着预测WM复合损失。
我们确定了CSF磷酸化tau与MC内WM下降之间的位点特异性关系。pT205处淀粉样蛋白沉积和Tau磷酸化的存在与WM复合物损失有关。这些发现强调了WM功能障碍的主要AD特异性机制，该机制与症状表现和认知能力下降密切相关。
