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Alzheimer Dementia :遗传性痴呆,认知减退速度各有不同

2021-12-09 Freeman MedSci原创

在症状出现后,年轻的ADADMCs下降得更快

APP、PSEN1和PSEN2基因的致病性突变导致Aβ1-42异构体的相对过度生产/清除不足,并且渗透率为100%,为AD病因学的淀粉样假说提供了支持。

最近,有常染色体显性遗传病(ADAD)风险的人作为参与者,在可预测的年龄肯定会发展成AD,这使得AD的二级预防试验得以进行,这允许用较少的参与者达到足够的力量。

这些治疗性试验包括一个假设,即这两种病症在某种程度上是相似的,也就是说,在预防ADAD方面发现有效的治疗性化合物也可能对预防LOAD有效。

然而,这些队列在认知方面的直接比较,是对潜在病理的间接测量,也是食品和药物管理指南推荐的治疗效果的一个重要指标(尽管他们最近对化合物阿杜卡单抗的决定有争议)是罕见的。

以前观察到的ADAD和LOAD之间的差异包括:患病率(<1%的AD与突变有关),症状发生的年龄(ADAD通常年轻数十年),以及神经病理检查时的合并症频率(ADAD较低)。ADAD和LOAD之间在临床、认知、影像、脑脊液(CSF)和神经病理测量方面有相似之处,但大多数研究只是间接地将ADAD与LOAD进行比较,而不是将ADAD和LOAD个体的数据纳入同一分析。

关于发病年龄(AAO)对有症状的LOAD临床进展的影响的文献是混合的,一些研究发现没有差异,发病年龄较小(<60或65岁)的临床疾病过程更具侵略性,或者发病年龄较小的临床过程更具侵略性。

方法上的差异可能导致混合的结果,因为AAO通常是自我报告的,随访期可能只有1到2年,缺乏神经病理学或生物标志物AD确认,以及任意年龄定义实验组(如<65岁;>65岁)。

LOAD组和ADAD组之间认知能力下降的临床前比较是罕见的,因为对LOAD的大型研究只在过去的≈15至18年中增加了生物标志物的收集(允许在症状出现之前检测发展中的病理)(如阿尔茨海默病神经影像学倡议[ADNI])。AAO对临床前下降率的影响目前还不清楚。


比较认知变化率的研究(尽管是间接的)常常发现年轻发病的AD,无论是否与突变有关,都比晚期发病的AD进展得更快。只有一项小型研究直接比较了ADAD和LOAD在症状出现后的认知下降。 Rosselli等人研究了哥伦比亚一个大型PSEN1(E280A)血统的受影响成员(n = 12)与LOAD患者(n = 10)的比较。由于年龄上的匹配是不可能的,各组在入院时的平均迷你精神状态检查(MMSE)得分和受教育年限上是匹配的。 在18个月的时间里,他们对阿尔茨海默病注册中心(CERAD)的神经心理学电池进行了三次管理,发现各组在基线上是相似的,但突变携带者(MCs)随着时间的推移下降得更快,特别是在MMSE上。这些研究的共同局限性包括缺乏对临床诊断准确性的尸检/生物标志物确认(即确认所有LOAD参与者有AD)以及没有临床前数据。

显性遗传阿尔茨海默病网络(DIAN,一项关于ADAD的国际纵向临床和生物标志物研究)的目的之一是比较ADAD与LOAD在症状出现前后的临床、认知和病理表型。DIAN的MCs继承了三个基因(PSEN1、PSEN2和APP)中的一个致病突变,具有高渗透性(几乎所有的人都会出现AD病症)。 使用国家阿尔茨海默氏症协调中心(NACC)的LOAD样本,可以纳入经尸检确认的AD神经病理学参与者。NACC样本作为DIAN MCs的LOAD比较组的其他好处是丰富的纵向数据和使用相同的临床和认知测试。

藉此,华盛顿大学的Virginia D. Buckles等人,利用DIAN和NACC数据,探究了ADAD突变携带者(MCs)和经尸检确认的LOAD个体的认知轨迹。

并比较了ADAD MCs(n = 310)和尸检证实的LOAD参与者(n = 163)在症状发生(估计/观察)之前和之后认知指标的纵向变化率。

他们发现:LOAD参与者在无症状期(临床前)下降得更快,在症状发生时比ADAD参与者在认知综合方面表现得更差

然而,在症状出现后,年轻的ADADMCs下降得更快。ADAD和LOAD的认知轨迹相似但不完全相同(下降但速度不同),说明AD的病理是共同的,但也有一些区别。



原文出处:
Buckles VD, Xiong C, Bateman RJ, et al. Different rates of cognitive decline in autosomal dominant and late‐onset Alzheimer disease. Alzheimer’s &amp; Dementia. Published online December 2, 2021:alz.12505. doi:10.1002/alz.12505

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    2021-12-09 1244c0ebm28暂无昵称

    学习学习

    0

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    2021-12-08 neuro.Dr

    老年性痴呆,未来还是希望借助神经电生理吧,也许更为有效!

    0

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低灌注的空间模式可能会区分 AD 和 VRF 相关对局部 CBF 的影响。

Alzheimer&Dementia:神经丝和颗粒体蛋白前体与额颞叶变性的萎缩有关

神经丝和颗粒体蛋白前体与结构成像相互作用确定为监测疾病进展和治疗的有希望的候选者。

JAMA neurology:从虚弱到痴呆有多远?美国和英国痴呆症前的虚弱轨迹

衰弱测量可用于识别高危人群,以便优先参加痴呆症预防和治疗的临床试验。

IJNS:护士主导的分阶段综合艺术认知干预对老年痴呆症患者的影响

这项由护士主导的分阶段综合艺术认知干预项目的随机对照试验中,参与该项目的阿尔茨海默病老年患者的认知能力和心理健康有所改善。

2022 欧洲共识:MCI和轻度痴呆初级阶段的诊断和治疗

意大利阿尔兹海默病专家组 · 2022-10-09

适合痴呆症患者的急救护理:老年急救护理应用研究网络范围审查和共识会议的结果

急性期后和长期护理学会(AMDA,The Society for Post-Acute and Long-Term Care Medicine) · 2022-08-01

痴呆及阿尔茨海默病进展要点简析

四川大学华西医院 · 2022-07-26

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