Toledo Jon B, Salmon David P, Armstrong Melissa J, Galasko Douglas
Stanley H. Appel Department of Neurology, Nantz National Alzheimer Center, Houston Methodist Hospital, Houston, TX, USA.
Shiley-Marcos Alzheimer's Disease Research Center, Department of Neurosciences, University of California, San Diego, CA, USA.
Alzheimers Res Ther. 2024 Dec 20;16(1):270. doi: 10.1186/s13195-024-01628-z.
Alzheimer's disease neuropathologic change (ADNC) and Lewy pathology (LP) often coexist in cognitively impaired individuals. These pathologies' relative distribution and severity may modify these individuals' clinical presentation, cognitive profile, and prognosis. Therefore, we examined the contributions of LP and concomitant ADNC to disease survival and profiles of cognitive decline in preclinical and clinical stages in a large neuropathologically diagnosed group.
We evaluated 597 participants with LP and 491 participants with intermediate/high ADNC in the absence of LP from the National Alzheimer Coordinating Center (NACC) database. At baseline, 237 participants were cognitively normal (CN), 255 were diagnosed with mild cognitive impairment (MCI), and 596 with dementia. Cognition was assessed using three cognitive domain scores (i.e., Memory, Executive, and Language) from the NACC Uniform Dataset (UDS) neuropsychological test battery, MMSE, and Clinical Dementia Rating (CDR). Multivariate adaptive regression splines were used to evaluate associations between baseline cognitive scores and mean annual rate of change over two years. The likelihood of progression to MCI or dementia was assessed using Cox hazard models.
Neocortical LP, independent of the clinical diagnosis, was associated with lower Executive and higher Language and Memory scores at baseline, whereas Braak V-VI neurofibrillary tangle pathology was associated with lower Memory and Language scores. Similarly, neocortical LP was associated with faster Executive decline, whereas Braak V-VI neurofibrillary tangle pathology was associated with faster Memory and Language decline. A clinical diagnosis of Lewy Body Dementia (i.e., a strong LP phenotype) was associated with the LP cognitive profile and shorter disease duration. Progression to incident MCI or dementia was primarily associated with the degree of tau pathology; neocortical LP or a diagnosis of Lewy Body Dementia only predicted progression when those with intermediate/high ADNC were excluded.
LP and ADNC differentially affected cross-sectional and longitudinal cognitive profiles in a large autopsy sample. Concomitant Braak V-VI neurofibrillary tangle pathology had a strong impact on clinical progression in those with LP, regardless of the initial stage. Thus, LB and ADNC co-pathology interact to affect cognitive domains that may be used to track Lewy Body disease longitudinally and as outcome measures in therapeutic trials.
阿尔茨海默病神经病理改变（ADNC）和路易体病理（LP）在认知受损个体中常同时存在。这些病理改变的相对分布和严重程度可能会改变这些个体的临床表现、认知特征和预后。因此，我们在一个经神经病理学诊断的大型队列中，研究了LP以及与之并存的ADNC在临床前期和临床阶段对疾病生存期和认知衰退特征的影响。
我们从国家阿尔茨海默病协调中心（NACC）数据库中评估了597例有LP的参与者和491例无LP的中度/高度ADNC参与者。基线时，237名参与者认知正常（CN），255名被诊断为轻度认知障碍（MCI），596名患有痴呆症。使用NACC统一数据集（UDS）神经心理测试组中的三个认知领域分数（即记忆、执行和语言）、简易精神状态检查表（MMSE）和临床痴呆评定量表（CDR）评估认知功能。使用多变量自适应回归样条来评估基线认知分数与两年内平均年变化率之间的关联。使用Cox风险模型评估进展为MCI或痴呆症的可能性。
新皮质LP与基线时较低的执行功能分数以及较高的语言和记忆分数相关，与临床诊断无关，而Braak V-VI神经原纤维缠结病理与较低的记忆和语言分数相关。同样，新皮质LP与执行功能衰退更快相关，而Braak V-VI神经原纤维缠结病理与记忆和语言衰退更快相关。路易体痴呆的临床诊断（即强烈的LP表型）与LP认知特征和较短的疾病持续时间相关。进展为新发MCI或痴呆症主要与tau病理程度相关；仅当排除中度/高度ADNC患者时，新皮质LP或路易体痴呆的诊断才预测疾病进展。
在一个大型尸检样本中，LP和ADNC对横断面和纵向认知特征有不同影响。无论初始阶段如何，并存的Braak V-VI神经原纤维缠结病理对有LP的患者的临床进展有强烈影响。因此，LB和ADNC共同病理相互作用，影响认知领域，这些领域可用于纵向追踪路易体病，并作为治疗试验中的结局指标。
