PDF(Pubmed)
Abstract：
Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer\'s Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.
摘要：
神经退行性病变，如阿尔茨海默病神经病理变化（ADNC），路易体病（LBD），边缘型年龄相关性TDP-43脑病神经病理变化（LATE-NC），和脑血管疾病（CVD）经常共存，但是，对于每种病理对混合病理受试者的认知能力下降和痴呆的确切贡献知之甚少。我们采用调整年龄的多变量逻辑回归分析，探讨了并发常见和罕见神经退行性病变的相对认知影响，性别,和教育水平。我们分析了来自国家阿尔茨海默氏症协调中心数据库的6262名受试者，每个人的神经病理学发现范围从0到6个共病，其中95.7%的个体在尸检时至少有1个神经退行性发现，75.5%的个体至少有2个神经退行性发现。我们确定了哪些神经病理学实体彼此最频繁地相关，并证明了每个个体的病理总数与通过临床痴呆评分（CDR®）和迷你精神状态检查（MMSE）评估的认知表现直接相关。我们证明了ADNC，LBD,LATE-NC,CVD,海马硬化,选择疾病，FTLD-TDP作为自变量显著影响整体认知。更具体地说,ADNC显著影响所有评估的认知领域，LBD影响注意力，处理速度,和语言,LATE-NC主要影响与逻辑记忆和语言相关的测试，而CVD和其他不太常见的病理(包括Pick病，进行性核上性麻痹,和皮质基底变性）具有更多可变的神经认知作用。此外,ADNC,LBD,和更高数量的共病神经病理与至少一个APOEε4等位基因的存在有关，ADNC和较高数量的神经病理学与APOEε2等位基因呈负相关。了解个体和伴随神经病理学影响认知的机制以及每种疾病的贡献程度是发展生物标志物和疾病修饰疗法的必要步骤。特别是随着这些医疗干预变得更加有针对性和个性化。
