Prospective validation and implementation of high-performing blood biomarkers and digital cognitive tests for detection of Alzheimer's disease in specialist memory clinic and primary care settings

前瞻性验证和实施高性能血液生物标志物和数字认知测试，用于在专业记忆诊所和初级保健机构中检测阿尔茨海默病

• 批准号: 10738367
• 负责人: Oskar Hansson
• 金额: $ 50万
• 依托单位: LUND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738367
• 关键词: Adopted; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease blood test; Alzheimer' s disease diagnosis; Alzheimer' s disease diagnostic; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Authorization documentation; Biological Assay; Biological Markers; Blood; Blood Tests; Brain; Caregivers; Caring; Cellular Phone; Cerebrospinal Fluid; Clinic; Clinical; Cognitive; Consensus; Country; Dementia; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Marker; Evaluation; Future; Goals; Healthcare; Hematological Disease; Immunoassay; Impaired cognition; Individual; Infrastructure; International; Intervention; Interview; Life; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Memory; Memory impairment; Methods; Neurobehavioral Manifestations; Neuropsychological Tests; Outcome; Paper; Patient Care; Patients; Persons; Physicians; Plasma; Population; Positron-Emission Tomography; Primary Care; Prospective Studies; Protocols documentation; Publishing; Recommendation; Reference Standards; Research; Research Personnel; Sampling; Specialist; Sweden; Tablets; Test Result; Testing; Time; Validation; Visit; authority; blood-based biomarker; care systems; clinical diagnostics; clinical implementation; clinical practice; cognitive testing; comorbidity; cost effective; diagnostic accuracy; diagnostic algorithm; digital; experience; improved; informant; mild cognitive impairment; novel; novel diagnostics; novel marker; patient prognosis; primary care setting; prognostic; prognostic algorithm; prognostic tool; prospective; recruit; speech recognition; tool; treatment as usual

SUMMARY The recent major breakthroughs in the development of accurate blood-based Alzheimer’s disease (AD) biomarkers, including phospho-tau217 (pTau217), have the potential to truly revolutionize AD diagnostics. However, these novel biomarkers must now be thoroughly validated in a prospective fashion in clinical practice before they can be implemented in the diagnostic and prognostic work-up of AD in specialist clinics and primary care globally. This validation is urgently needed because of the relatively low accuracy of the clinical diagnostic work-up without support of accurate AD biomarkers, resulting in misdiagnoses of 25-30% of AD patients in specialist memory clinics and >50% in primary care. Furthermore, it is important to determine in which patients and real-world clinical settings these novel blood AD biomarkers clearly improve diagnosis, treatment, and care, which is essential for reimbursement in many countries. Finally, we also need accurate prognostic tools to identify those individuals with early AD who are most likely to show imminent clinical decline, because this group may benefit most from targeted interventions. This is highly timely considering the recent advent of disease-modifying AD therapies that may soon become widely available. Given the excellent infrastructure of the primary care system in Sweden and research biomarker protocols already approved and fully integrated in clinical practice, we have a unique opportunity to test these novel blood AD markers in broad, diverse, and unselected populations that are generalizable to other real-world settings. To achieve this ambitious goal, we will conduct two novel and unique prospective studies in specialist memory clinic (n=800) and general primary care (n=800) settings. First, we aim to prospectively validate plasma AD biomarkers for the diagnosis of patients with cognitive symptoms evaluated in either specialist memory clinics or in primary care. Following recent expert consensus recommendations, we will use i) predefined biomarker cut-offs, ii) bi- weekly analysis of the plasma samples and iii) appropriate reference standards (i.e., PET/CSF). We anticipate that we will identify - within 48 months - AD blood biomarkers with high potential for implementation in memory clinic and/or primary care settings. Second, we will determine whether blood-based AD biomarkers improve patient management in specialist memory clinic settings and general primary care settings. Demonstrating improvements of the AD diagnostic work-up and treatment when compared to “care-as-usual” is essential for regulatory authorities to approve future reimbursement of blood-based biomarkers. Third, we aim to optimize the prognosis of patients with early AD by combining (prospectively analyzed) plasma AD biomarkers with brief digital cognitive tests. The expected outcome is a combination of easily accessible and time- and cost-effective blood biomarkers and digital cognitive tests that can predict short-term cognitive decline and progression to AD dementia in primary care. At the end of this project, our expected goal is that blood-based biomarkers and prognostic algorithms will be ready for clinical implementation in both specialist clinics and primary care.

概括 最近在精确的基于血液的阿尔茨海默病（AD）生物标志物的开发方面取得了重大突破， 包括磷酸化 tau217 (pTau217)，有可能真正彻底改变 AD 诊断。 新的生物标志物现在必须在临床实践中以前瞻性的方式进行彻底验证，然后才能被应用 在全球专科诊所和初级保健中实施 AD 的诊断和预后检查。 由于临床诊断检查的准确性相对较低，因此迫切需要验证 支持准确的 AD 生物标志物，导致专业记忆中 25-30% 的 AD 患者误诊 诊所和初级保健中的比例超过 50% 此外，确定哪些患者和现实世界的临床也很重要。 这些新型血液 AD 生物标志物明显改善了诊断、治疗和护理，这对于 最后，我们还需要准确的预后工具来识别那些患有此病的人。 早期 AD 最有可能表现出即将出现的临床衰退，因为该群体可能从靶向治疗中受益最多 考虑到最近出现的改变疾病的 AD 疗法可能很快就会出现，这是非常及时的。 变得广泛可用。 鉴于瑞典初级保健系统的优良基础设施和研究生物标志物协议 已经获得批准并完全融入临床实践，我们有一个独特的机会来测试这些新型血液 广泛、多样化且未经选择的人群中的 AD 标记可推广到其他现实世界环境。 为了实现这一雄心勃勃的目标，我们将在专业记忆诊所进行两项新颖且独特的前瞻性研究 (n=800) 和一般初级保健 (n=800) 设置首先，我们的目标是前瞻性验证血浆 AD 生物标志物。 用于在专业记忆诊所或初级诊所评估的具有认知症状的患者的诊断 根据最近的专家共识建议，我们将使用 i) 预定义的生物标志物截止值，ii) 双- 每周分析血浆样本和 iii) 适当的参考标准（即 PET/CSF）。 我们将在 48 个月内确定 AD 血液生物标志物，该标志物在记忆诊所中具有很高的应用潜力 其次，我们将确定基于血液的 AD 生物标志物是否可以改善患者的情况。 专业记忆诊所环境和普通初级保健环境的管理得到改善。 与“照常护理”相比，AD 诊断检查和治疗的质量对于监管机构至关重要 第三，我们的目标是优化患者的预后。 通过将（前瞻性分析）血浆 AD 生物标志物与简短的数字认知测试相结合，来诊断早期 AD。 预期结果是易于获取且具有时间和成本效益的血液生物标志物和数字化的组合 认知测试可以预测初级保健中短期认知能力下降和 AD 痴呆的进展。 在该项目结束时，我们的预期目标是基于血液的生物标志物和预后算法将被 准备好在专科诊所和初级保健中进行临床实施。