Project 1 - The Frontotemporal Lobar Degeneration Clinical Research Consortium

最有希望的FTLD新疗法将靶向与大多数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挑战是无法预测大多数不携带已知致病突变的FTLD病例的潜在病理学。在这些散发病例中，与潜在tau病理学最强的临床病理学关联是进行性核上性麻痹综合征（PSPS）。对于TDP-43病理学，最强的关联是语义变异型原发性进行性失语症（svPPA）和额颞叶痴呆伴肌萎缩侧索硬化症（FTD-ALS）。本研究项目的主要目标是确定这些综合征临床试验入组的障碍，以创建一个具有可预测基础病理学的符合临床试验条件的FTLD患者的良好特征化队列。最近的证据还表明，由于肿瘤坏死因子α（TNF α）信号传导失衡引起的全身性炎症可能在tDP-43 FTLD中发挥作用。这项横断面研究将从在线FTLD CRC患者登记处招募650名svPPA、FTD-ALS和PSPS患者，这些患者将在最近的FTLD CRC临床研究中心或已在这些研究中心随访的患者中接受评价。所有个体都将接受专家FTLD CRC研究者的诊断评估，包括已知FTLD导致突变的基因分型，新的FTLD特异性评估组合（FTLD模块）以及评估生活质量和影响临床试验资格因素的问卷调查。此外，将使用标准多重ELISA测定法测量血浆细胞因子水平，以评估是否应将抗TNF-α药物作为svPPA和FTD-ALS的潜在治疗。我们的目标是：1）估计可实现的样本量，并确定关键的散发性FTLD临床试验人群（svPPA、FTD-ALS和PSPS）参与临床试验的最重要障碍; 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之间的关联。

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.