Neuroscience Group of Antioquia, Faculty of Medicine, University of Antioquia, Medellín, Colombia.
Lancet Neurol. 2011 Mar;10(3):213-20. doi: 10.1016/S1474-4422(10)70323-9. Epub 2011 Feb 4.
Mild cognitive impairment (MCI) and pre-MCI have been proposed as stages preceding Alzheimer's disease (AD) dementia. We assessed descendants of individuals with a mutation in presenilin 1 (PSEN1) that causes familial AD, with the aim of identifying distinct stages of clinical progression to AD dementia.
We retrospectively studied a cohort of descendants of carriers of the PSEN1 E280A mutation. Pre-dementia cognitive impairment was defined by a score 2 SD away from normal values in objective cognitive tests, and was subdivided as follows: asymptomatic pre-MCI was defined by an absence of memory complaints and no effect on activities of daily living; symptomatic pre-MCI was defined by a score on the subjective memory complaints checklist higher than the mean and no effect on activities of daily living; and MCI was defined by a score on the subjective memory complaints checklist higher than the mean, with no effect on basic activities of daily living and little or no effect on complex daily activities. Dementia was defined according to the diagnostic and statistical manual of mental disorders, fourth edition. Reference mean scores were those of participants who did not carry the PSEN1 E280A mutation. We used the Turnbull survival analysis method to identify ages at onset of each stage of the disease. We measured the time from birth until onset of the three pre-dementia stages, dementia, and death, and assessed decline in cognitive domains for each stage.
Follow-up was from Jan 1, 1995, to Jan 27, 2010. 1784 patients were initially identified, 449 of whom were PSEN1 E280A carriers who had complete clinical follow-up. Median age at onset was 35 years (95% CI 30-36) for asymptomatic pre-MCI, 38 years (37-40) for symptomatic pre-MCI, 44 years (43-45) for MCI, and 49 years (49-50) for dementia. The median age at death was 59 years (95% CI 58-61). The median time of progression from asymptomatic to symptomatic pre-MCI was 4 years (95% CI 2-8), from symptomatic pre-MCI to MCI was 6 years (4-7), from MCI to dementia was 5 years (4-6), and from dementia to death was 10 years (9-12). The cognitive profile was predominantly amnestic and was associated with multiple domains. Affected domains showed variability in initial stages, with some transient recovery in symptomatic pre-MCI followed by continuous decline.
Clinical deterioration can be detected as measurable cognitive impairment around two decades before dementia onset in PSEN1 E280A carriers. Onset and progression of pre-dementia stages should be considered in the investigation and use of therapeutic interventions for familial AD.
Departamento Administrativo de Ciencia, Tecnología e Innovación, COLCIENCIAS, Republic of Colombia.
轻度认知障碍（MCI）和前 MCI 被认为是阿尔茨海默病（AD）痴呆的前期阶段。我们评估了携带早老素 1（PSEN1）基因突变的个体的后代，旨在确定向 AD 痴呆临床进展的不同阶段。
我们回顾性研究了携带 PSEN1 E280A 突变的携带者的后代队列。认知障碍前定义为客观认知测试得分低于正常 2 个标准差，分为以下几类：无症状前 MCI 定义为无记忆障碍且对日常生活活动无影响；有症状前 MCI 定义为主观记忆障碍清单得分高于平均值且对日常生活活动无影响；MCI 定义为主观记忆障碍清单得分高于平均值，对基本日常生活活动无影响或影响较小，对复杂日常活动影响较小。痴呆症根据《精神障碍诊断和统计手册》第四版定义。参考平均分数为未携带 PSEN1 E280A 突变的参与者的分数。我们使用特恩布尔生存分析方法来确定疾病每个阶段的发病年龄。我们测量了从出生到三个认知障碍前阶段、痴呆症和死亡的时间，并评估了每个阶段认知领域的下降情况。
随访时间为 1995 年 1 月 1 日至 2010 年 1 月 27 日。最初确定了 1784 名患者，其中 449 名为 PSEN1 E280A 携带者，他们有完整的临床随访。无症状前 MCI 的发病中位年龄为 35 岁（95%CI 30-36），有症状前 MCI 为 38 岁（37-40），MCI 为 44 岁（43-45），痴呆症为 49 岁（49-50）。死亡的中位年龄为 59 岁（95%CI 58-61）。从无症状到有症状前 MCI 的中位进展时间为 4 年（95%CI 2-8），从有症状前 MCI 到 MCI 为 6 年（4-7），从 MCI 到痴呆症为 5 年（4-6），从痴呆症到死亡为 10 年（9-12）。认知特征主要为遗忘型，与多个领域相关。受影响的领域在初始阶段表现出变化，在有症状前 MCI 中有一些短暂的恢复，随后持续下降。
在 PSEN1 E280A 携带者中，在痴呆症发病前约二十年就可以检测到可测量的认知障碍，从而导致临床恶化。在对家族性 AD 进行调查和使用治疗干预措施时，应考虑认知障碍前阶段的发病和进展。
科学、技术和创新管理部，哥伦比亚国家科学技术委员会，哥伦比亚共和国。
