Determinants of Neurodegenerative Decline in Primary Progressive Aphasia

原发性进行性失语症神经退行性衰退的决定因素

• 批准号: 8443796
• 负责人: EMILY J ROGALSKI
• 金额: $ 33.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443796
• 关键词: Address; Alzheimer' s Disease; Amyloid; Anatomy; Area; Atrophic; Autopsy; Benchmarking; Biological Markers; Biometry; Brain; Brain Diseases; Clinical; Clinical Treatment; Clinical Trials; Cognitive; Collaborations; Comprehension; Data; Dementia; Development; Differential Diagnosis; Disease; Disease Marker; Disease Progression; Elderly; Etiology; Family; Frontotemporal Lobar Degenerations; Funding; Future; Goals; Image; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Language; Letters; Life; Location; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Measures; Medial; Memory; Methods; Monitor; National Institute on Deafness and Other Communication Disorders; Nature; Nerve Degeneration; Neurobiology; Neuropsychological Tests; Neuropsychology; Outcome; Outcome Measure; Pathology; Patients; Pattern; Performance; Phenotype; Physics; Population; Positron-Emission Tomography; Primary Progressive Aphasia; Procedures; Radiopharmaceuticals; Reporting; Research Personnel; Series; Severities; Site; Staging; Symptoms; Syndrome; Testing; Therapeutic; Therapy Clinical Trials; Time; Universities; Variant; Visit; amyloid imaging; base; cerebral atrophy; clinical phenotype; clinically relevant; cognitive change; functional decline; high risk; in vivo; interest; longitudinal course; mild cognitive impairment; neurobehavior; neuroimaging; neuropathology; neuropsychological; novel therapeutics; patient expectation; success; treatment effect; treatment strategy; treatment trial

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.

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。虽然功能下降不可避免地发生，但影响PPA患者功能下降时间和症状严重程度的因素尚未完全阐明。此外，PPA与两种主要的潜在病理相关：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性质。大量的尸检系列，包括我们中心的一个尸检系列，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，临床和解剖学特征的可靠鉴定的基础病理