Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium.
Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Neuroimage Clin. 2019;22:101771. doi: 10.1016/j.nicl.2019.101771. Epub 2019 Mar 13.
Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on F-FDG SUVR. CSF measures included Aβ, Aβ, T-tau, P-tau, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p < 0.001] and + 0.37 [p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aβ burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: β = -0.28 [p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.
疾病修饰治疗试验越来越先进到阿尔茨海默病（AD）的前驱期或临床前阶段，纳入标准基于生物标志物而非临床症状。因此，确定哪些生物标志物应该结合起来以准确预测从轻度认知障碍（MCI）到 AD 痴呆的转化非常重要。然而，迄今为止，只有少数研究使用脑脊液（CSF）和成像标志物中的每一种对 A/T/N 受试者进行了完整的特征描述，或者仅研究了长期（≥2 年）预后。本研究旨在探讨基线时脑脊液（CSF）、磁共振成像（MRI）、淀粉样蛋白和 F-FDG 正电子发射断层扫描（PET）测量值与认知变化和在短期（12 个月）内转化为 AD 痴呆之间的关系。我们纳入了 13 名健康对照者、49 名 MCI 和 16 名 AD 痴呆患者，这些患者基于临床诊断和基线时的完整 A/T/N 特征描述。使用两种不同的参考区域（小脑灰质和皮质下白质）的 F-AV45 标准化摄取比值（SUVR）来量化全脑皮质淀粉样蛋白-β（Aβ）负荷，而代谢则基于 F-FDG SUVR 进行评估。CSF 测量包括 Aβ、Aβ、T-tau、P-tau 及其比值，MRI 标志物包括海马体积（HV）、脑白质高信号和皮质灰质体积。认知功能通过 MMSE 和 RBANS 指数评分进行测量。所有统计分析均校正了年龄、性别、教育程度和 APOE ε4 基因型。结果表明，与代谢功能减退（后扣带回）和海马体积较小（例如，故事回忆的变化：β=+0.43[ p<0.001]和+0.37[ p=0.005]）相比，认知衰退较快与基线时的 Aβ负荷增加相关性更强。此外，只有当 SUVR 参考皮质下白质时，基线时 Aβ 负荷较高与认知衰退较快显著相关（例如，故事回忆的变化：β= -0.28[ p=0.020]）。MCI 患者每年转化为 AD 痴呆的速度为 31%，这可以通过将神经心理学测试（视觉空间构建技能）与 MRI 海马体积或 F-FDG-PET 相结合来最佳预测。将所有三个标志物结合起来，特异性为 96%，敏感性为 92%。淀粉样蛋白-PET 和 CSF 生物标志物均不能区分短期转化者和非转化者。
