Supplementary Material for: Neuroimaging and Biochemical Markers in the Three Variants of Primary Progressive Aphasia

<b><i>Background/Aim:</i></b> To investigate in variants of primary progressive aphasia (PPA) the association between current clinical and neuroimaging criteria and biochemical/genetic markers at the individual level. <b><i>Methods:</i></b> Thirty-two PPA patients were classified as non-fluent/agrammatic (nfvPPA), semantic (svPPA), or logopenic variant (lvPPA) or as unclassifiable (uPPA). In all patients, we evaluated the neuroimaging criteria (magnetic resonance imaging and/or single photon emission computed tomography/positron emission tomography) of each variant and studied serum progranulin levels, <i>APOE</i> genotype and Alzheimer’s disease (AD)-cerebrospinal fluid (CSF) biomarkers. Cases with a first-degree family history of early-onset dementia were genetically tested. <b><i>Results:</i></b> Ten of 15 (66%) nfvPPA, 5/5 (100%) svPPA and 7/7 (100%) lvPPA patients showed at least one positive neuroimaging-supported diagnostic criterion. All lvPPA and 3/5 (60%) uPPA patients presented AD-CSF biomarkers, which were absent in nfvPPA and svPPA cases. Four (27%) nfvPPA patients had dementia-causing mutations: 2 carried a <i>GRN</i> mutation and 2 the <i>C9ORF72</i> hexanucleotide expansion. <b><i>Conclusions:</i></b> There was an excellent association between clinical criteria and neuroimaging-supported biomarkers in svPPA and lvPPA, as well as with AD-CSF biochemical markers in the lvPPA. Neuroimaging, biochemical and genetic findings in nfvPPA were heterogeneous. Incorporating biochemical/genetic markers into the PPA clinical diagnosis would allow clinicians to improve their predictions of PPA neuropathology, especially in nfvPPA and uPPA cases.

**背景与目的：** 探究原发性进行性失语（primary progressive aphasia, PPA）各亚型中，个体水平的当前临床及神经影像诊断标准与生化/遗传标志物之间的关联。

**方法：** 将32例PPA患者分为非流利型/语法缺失型（nfvPPA）、语义型（svPPA）、找词困难型（lvPPA）或未分类型（uPPA）。对所有患者评估各亚型的神经影像诊断标准，包括磁共振成像（magnetic resonance imaging, MRI）和/或单光子发射计算机断层扫描（single photon emission computed tomography, SPECT）/正电子发射断层扫描（positron emission tomography, PET），并检测其血清颗粒蛋白前体水平、载脂蛋白E（APOE）基因型及阿尔茨海默病（Alzheimer’s disease, AD）脑脊液（cerebrospinal fluid, CSF）生物标志物。对于存在早发性痴呆一级亲属家族史的病例，进一步开展基因检测。

**结果：** 15例非流利型/语法缺失型PPA患者中有10例（66%）、5例语义型PPA患者全部（100%）及7例找词困难型PPA患者全部（100%）满足至少1项经神经影像支持的诊断标准。所有找词困难型PPA患者及3/5（60%）未分类型PPA患者均检出AD脑脊液生物标志物，而非流利型/语法缺失型及语义型PPA患者均未检出该类标志物。27%（4例）的非流利型/语法缺失型PPA患者携带致痴呆突变：2例携带有GRN基因突变，2例携带有C9ORF72六核苷酸重复扩增。

**结论：** 语义型与找词困难型PPA的临床诊断标准与经神经影像支持的生物标志物之间存在极佳的相关性，且找词困难型PPA还与AD脑脊液生化标志物显著相关。非流利型/语法缺失型PPA的神经影像、生化及遗传检测结果存在异质性。将生化/遗传标志物纳入PPA的临床诊断体系，可帮助临床医师更精准地预测患者的PPA神经病理分型，尤其针对非流利型/语法缺失型及未分类型PPA患者。