Determinants of Neurodegenerative Decline in Primary Progressive Aphasia

描述(申请人提供)：原发性进行性失语(PPA)是一种由神经退行性脑疾病引起的临床痴呆综合征，以语言障碍为主要特征。虽然功能衰退总是会发生，但影响PPA功能衰退的时间进程和症状严重程度的因素尚未完全阐明。此外，PPA与两种基本的病理类型有关：阿尔茨海默病(PPA-AD)和额颞叶变性(PPA-FTLD)病理，但目前还没有可靠的体内方法来确定病理的性质。许多尸检系列，包括我们中心的一个，表明大约30%的PPA表型病例有PPA-AD病理，而另外70%的病例有PPA-FTLD病理。然而，可靠地识别潜在病理的临床和解剖学特征 活着的病人仍然是一个持续的挑战。拟议的研究旨在建立疾病病因和进展的潜在标记物。具体目标包括：1)在18个月的时间内每隔6个月使用磁共振成像跟踪40名PPA综合征患者，以量化和描述脑萎缩随时间的变化；2)确定认知变化与萎缩的数量和位置之间的时间关系；以及3)使用新的[18F]-AV-45 PET成像化合物来确定PPA患者的淀粉样蛋白负荷作为AD病理的标志，并确定其与萎缩的关系。局部(即内侧颞叶)萎缩的纵向比率在预测阿尔茨海默病类型的遗忘性痴呆的认知能力下降方面是有用的。因此，我们预测与语言相关的大脑区域的萎缩率将有助于PPA的鉴别诊断和疾病进展的监测，可能为临床试验的结果测量指明方向。将确定与淀粉样蛋白负荷相关的临床、认知和解剖学特征。该项目的数据将确定萎缩的时间进展是否与认知能力下降、原发萎缩的解剖位置或基于淀粉样蛋白负荷的假定潜在病理有关。这个项目是首次使用新的生前淀粉样蛋白生物标记物[18F]-AV-45对PPA的纵向过程进行多维研究。除了他们的理论兴趣，这项研究的结果对于确定疾病类型和进展的客观生物标记物至关重要，这将为这一相对服务不足的痴呆症人群的治疗策略提供信息。该项目的结果还将填补我们对PPA患者萎缩模式与临床进展和潜在病理之间关系的认识空白。目标1中的方法是由萎缩模式驱动的，没有临床偏见，而目标2和3分别考虑了与认知表现和淀粉样蛋白阳性的关系。这对于提高我们将患者分配到治疗试验中的准确性具有相当重要的意义。

DESCRIPTION (provided by applicant): Primary progressive aphasia (PPA) is a clinical dementia syndrome caused by neurodegenerative brain disease, with language impairment as the primary feature. Although functional decline invariably occurs, the factors influencing the time course of decline and severity of symptoms in PPA have not been fully elucidated. Furthermore, PPA is associated with two main classes of underlying pathology: Alzheimer pathology (PPA-AD) and frontotemporal lobar degeneration (PPA-FTLD) pathology, but there is currently no reliable in vivo method for identifying the nature of the pathology. Numerous autopsy series, including one from our Center, indicate that approximately 30% of cases with the PPA phenotype have PPA-AD pathology while the other 70% show PPA-FTLD pathology. However, the reliable identification of clinical and anatomical features of underlying pathology in living patients remains an ongoing challenge. The proposed studies are directed at establishing potential markers for disease etiology and progression. The Specific Aims include: 1) To follow 40 patients with the PPA syndrome using MR imaging at 6-month intervals over an 18-month time period to quantify and characterize how brain atrophy changes over time; 2) to determine the temporal relationship between cognitive change and the quantity and location of atrophy; and 3) to use the new [18F]-AV-45 PET imaging compound to identify amyloid burden in PPA patients as a marker of AD pathology and to identify its relationship to atrophy. Longitudinal rates of regional (i.e., medial temporal) atrophy have been useful in predicting cognitive decline in the amnestic dementia of the Alzheimer's type. Therefore, we predict that atrophy rates in language related brain areas will be useful in differential diagnosis and monitoring of disease progression in PPA, potentially pointing the way to an outcome measure for clinical trials. The clinical, cognitive and anatomical features associated with amyloid burden will be identified. Data from this project will determine whether the temporal progression of atrophy is related to cognitive decline, anatomical site of primary atrophy, or putative underlying pathology based on amyloid burden. This project represents the first multidimensional study of longitudinal course using the new antemortem amyloid biomarker [18F]-AV-45 in PPA. In addition to their theoretical interest, the results from this study are of crucial importance for defining objective biomarkers of disease type and progression, which will inform therapeutic treatment strategies for this relatively underserved dementia population. Results from this project will also fill gaps n our knowledge of the relationship between atrophy patterns and both clinical progression and underlying pathology in patients with PPA. The approach in Aim 1 is driven by atrophy patterns and free of clinical bias, while Aims 2 and 3 consider the relationship with cognitive performance and amyloid positivity, respectively. This is of considerable importance for increasing the accuracy with which we assign patients to therapeutic trials.