Alzheimer-like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46
Alzheimer-like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46
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临床前老年出生队列中的阿尔茨海默样生物标志物异质性：Insight46
DOI：
10.1002/alz.067555
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Garcia M
中科院分区：
文献类型：
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作者：
Garcia M
背景阿尔茨海默病(AD)的两个主要复杂性是在症状出现前10年或更长时间内发生的病理改变(如淀粉样蛋白积聚)，以及AD是一种高度异质性的疾病，具有多种临床亚型。子类型和阶段推理(维护)，一种数据驱动的建模技术，以前已经应用于ADNI，以更好地理解AD。在这里，我们将Support应用于Insight46，这是英国1946年出生队列的一个子研究，以检测临床前神经退行性变的不同轨迹。方法将SuStain应用于来自466名研究成员的横断面MRI、淀粉样蛋白PET、血浆生物标记物和认知(临床前阿尔茨海默病认知复合体[PACC])(表1)。376名淀粉样蛋白阴性个体(计算为Lane等人。2019年)被指定为对照组。ADNI中也估计了持续亚型(N=789；表1和表2)以供比较。使用t检验和卡方检验来评估基线APOE、淀粉样蛋白状态、白质高强度体积(WMHV)以及使用边界移位积分计算的全脑、脑室和海马区体积变化率的亚型差异。结果图1显示了维护发现的三种亚型：典型的、皮质下的和皮质的。典型的亚型似乎反映了典型的AD进展模式，早期受累于β40/42比值和神经丝光(NFL)，其次是PAcc，最后是血浆tau。MRI的体积改变出现的时间较晚。“皮质下”亚型和“皮质”亚型的特点都是早期核磁共振体积异常。图2显示，被分配到“皮质”亚型的受试者的WMHV显著高于其他两个亚型(p-Value<；0.002)。图3显示与皮质下亚型相比，典型亚型脑室扩张和全脑萎缩的发生率显著更高(p值=0.001)。结论本研究揭示了三种不同的亚型(典型、皮质下和皮质下)在老年临床前队列中推定的神经变性；这些与AD患者队列中发现的一致，例如ADNI，这意味着这些方法可能在基于人群的队列中有用。这些结果表明，维持剂可能有助于在非常早期阶段确定神经退行性变的不同亚型，并对临床试验的招募和支持产生影响。
BackgroundTwo main complexities of Alzheimer’s Disease (AD) arise from pathological changes (such as amyloid accumulation) occurring a decade or more before symptom onset, and AD being a highly heterogeneous disease with various clinical subtypes. Subtype and Stage Inference (SuStaIn), a data‐driven modelling technique, has been previously applied to ADNI to better understand AD. Here we apply SuStaIn to Insight46, a sub‐study of the British 1946 Birth Cohort to detect different trajectories of preclinical neurodegeneration.MethodSuStaIn was applied to cross‐sectional MRI, amyloid PET, plasma biomarkers, and cognition (Preclinical Alzheimer Cognitive Composite [PACC]) from 466 study members (Table 1). 376 Amyloid‐negative individuals (computed asLane et al. 2019) were designated as controls. SuStaIn subtypes were also estimated in ADNI (N=789; Tables 1 and 2) for comparison. T‐tests and Chi‐squared tests were used to assess subtype differences in baseline APOE, amyloid status, white matter hyperintensity volume (WMHV), and rates of change in whole brain, ventricular and hippocampal volume calculated using the boundary shift integral.ResultFigure 1 shows three subtypes uncovered by SuStaIn: ‘Typical’, ‘Subcortical’ and ‘Cortical’. The ‘Typical’ subtype appears to reflect a typical AD progression pattern, with early involvement of Aβ40/42ratio and Neurofilament light (NFL), followed by the PACC and finally, plasma tau. MRI volumetric changes appear later. Both ‘Subcortical’ and ‘Cortical’ subtypes are characterised by earlier abnormality in MRI volumes.Figure 2 shows that subjects assigned to the ‘Cortical’ subtype had significantly higher WMHV than the other two subtypes (p‐value < 0.002). No other significant differences in baseline characteristics were found.Figure 3 shows ‘Typical’ subtype has significantly higher rates of ventricular expansion and whole brain atrophy compared with ‘Subcortical’ subtype (p‐values = 0.001).ConclusionThis study reveals three different subtypes (‘Typical’, ‘Subcortical’ and ‘Cortical’) of presumed neurodegeneration in an elderly, preclinical cohort; these are consistent with those found in AD patient cohorts, e.g. ADNI, meaning that these methods may have utility in population based cohorts. These results suggest that SuStaIn may be helpful in determining different subtypes of neurodegeneration at a very early stage with implications for recruitment to, and powering of, clinical trials.