Project 1 - The Frontotemporal Lobar Degeneration Clinical Research Consortium

最有希望的FTLD新疗法将针对与大多数FTLD病例相关的特定蛋白质：tau和tar DNA结合蛋白43(TDP-43)。用这种药物进行临床试验的一个挑战是无法预测大多数FTLD病例的潜在病理，这些病例没有携带已知的致病突变。在这些零星病例中，与tau的潜在病理联系最强的是进行性核上性麻痹综合征(PSPS)。对于TDP-43病理学，最强烈的关联是语义变异的原发性进行性失语症(SvPPA)和额颞部痴呆合并肌萎缩侧索硬化症(FTD-ALS)。这项研究项目的主要目标是确定在这些综合征中进行临床试验登记的障碍，以创建一个具有良好特征的符合临床试验条件的FTLD患者队列，并具有可预测的潜在病理。最近的证据还表明，由于肿瘤坏死因子α(TNFa)信号的失衡而引起的全身炎症可能在TDP-43FTLD中发挥作用。这项横断面研究将从在线FTLD CRC患者登记中招募650名svPPA、FTD-ALS和PSPS患者，他们将在最近的FTLD CRC临床站点进行评估，或从这些站点已经跟踪的患者中进行评估。所有个体都将接受FTLD CRC专家的诊断评估，包括已知FTLD导致突变的基因分型，新的FTLD专用评估单元(FTLD模块)，以及评估生活质量和影响临床试验资格的因素的问卷调查。此外，还将使用标准的多重酶联免疫吸附试验测定血浆细胞因子水平，以评估是否应该将抗肿瘤坏死因子-α药物作为svPPA和FTD-ALS的潜在治疗方法。我们的目标是：1)估计可实现的样本量，并确定关键的临床试验参与障碍，包括散发性FTLD临床试验人群svPPA、FTD-ALS和PSPS；2)确定携带已知FTLD相关突变的散发性svPPA、FTD-ALS和PSPS患者的百分比；3)检查自身免疫性疾病和促炎细胞因子水平与svPPA、FTD-ALS和PSPS之间的关系。

The most promising new therapies for FTLD will target specific proteins that are associated with the majority of FTLD cases: tau and TAR DNA binding protein 43 (TDP-43). A challenge for conducting clinical trials with such agents is the inability to predict the underlying pathology in the majority of FTLD cases who do not carry a known causative mutation. Of these sporadic cases, the strongest clinical-pathological association for underlying tau pathology is for Progressive Supranuclear Palsy syndrome (PSPS). For TDP-43 pathology, the strongest associations are for semantic variant Primary Progressive Aphasia (svPPA) and frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS). The major goal of this research project is to determine the barriers to clinical trial enrollment in these syndromes to create a wellcharacterized cohort of clinical trial-eligible FTLD patients with predictable underlying pathology. Recent evidence also suggests that systemic inflammation due to imbalances in Tumor Necrosis Factor alpha (TNFa) signaling may play a role in tDP-43 FTLD. This cross-sectional study will recruit 650 svPPA, FTD-ALS and PSPS patients from the online FTLD CRC patient registry who will be evaluated at the nearest FTLD CRC clinical site, or from patients already followed at these sites. All individuals will undergo a diagnostic evaluation by an expert FTLD CRC investigator including genotyping for known FTLD-causing mutations, a new FTLD-specific assessment battery (the FTLD Module), as well as questionnaires assessing quality of life and factors that affect clinical trial eligibility. In addition, plasma cytokine levels will be measured using a standard multiplexed ELISA assay to assess whether anti-TNF-alpha drugs should be pursued as a potential treatment for svPPA and FTD-ALS. We aim to: 1) estimate the achievable sample sizes and identify the most important barriers to clinical trial participation for key the sporadic FTLD clinical trial populations, svPPA, FTD-ALS and PSPS; 2) determine the percentage of sporadic svPPA, FTD-ALS and PSPS patients who carry known FTLD-associated mutations; 3) examine the association between autoimmune disease and pro-inflammatory cytokine levels and svPPA, FTD-ALS and PSPS.