Canan Fatih, Wick Neda, Raisanen Jack M, Burns Dennis K, Hatanpaa Kimmo J, Richardson Timothy E, White Charles L, Daoud Elena V
Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
J Alzheimers Dis. 2025 Aug 10;107(2):13872877251362762. doi: 10.1177/13872877251362762.
BackgroundDown syndrome (DS) is frequently associated with Alzheimer's disease neuropathologic change (ADNC). However, studies assessing the full spectrum of neurodegenerative pathologies using modern consensus and staging criteria remain limited.ObjectiveWe aimed to elucidate the progression of neurodegenerative pathologies in DS and to explore the prevalence of comorbid pathologies across a broad age range (0-76 years), using comprehensive neuropathological assessments.MethodsWe conducted a two-phase analysis. First, we investigated an institutional dataset, followed by a pooled analysis incorporating data from the National Alzheimer's Coordinating Center and four published studies. Pathologies assessed included amyloid-β (Aβ), tau, α-synuclein, TDP-43, cerebral amyloid angiopathy (CAA), other cerebrovascular diseases (CVD), hippocampal sclerosis (HS), and basal ganglia mineralizations (BGM).ResultsDiffuse Aβ plaques appeared by age 11, with neuritic plaques emerging in the mid-thirties. Mild tau pathology, including pre-tangles and neuropil threads, first emerged in the second decade, with neurofibrillary tangles fully present in the fourth decade, always concurrent with Aβ plaques. All individuals over 30 exhibited ADNC. α-Synuclein pathology was observed in 27% of cases, while aging-related tau astrogliopathy (ARTAG), HS, and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were rare. CVD was present in approximately 60%, CAA was nearly universal (98%) after age 50, and 18% had BGM. Brain weight was consistently below the 25th percentile, even in younger individuals without ADNC.ConclusionsDS shows a distinct neurodegenerative trajectory with early Aβ deposition. CAA, arteriolosclerosis, BGM, and α-synuclein pathology were highly prevalent, while ARTAG and LATE-NC were infrequently observed.
背景
唐氏综合征（DS）常与阿尔茨海默病神经病理改变（ADNC）相关。然而，使用现代共识和分期标准评估神经退行性病变全谱的研究仍然有限。
目的
我们旨在通过全面的神经病理学评估，阐明DS中神经退行性病变的进展，并探讨广泛年龄范围（0 - 76岁）内合并病变的患病率。
方法
我们进行了两阶段分析。首先，我们调查了一个机构数据集，随后进行汇总分析，纳入了来自国家阿尔茨海默病协调中心和四项已发表研究的数据。评估的病变包括淀粉样β蛋白（Aβ）、tau蛋白、α-突触核蛋白、TDP-43、脑淀粉样血管病（CAA）、其他脑血管疾病（CVD）、海马硬化（HS）和基底节矿化（BGM）。
结果
弥漫性Aβ斑块在11岁时出现，神经炎斑块在三十多岁时出现。轻度tau病理改变，包括前缠结和神经毡丝，最早在第二个十年出现，神经原纤维缠结在第四个十年完全出现，且总是与Aβ斑块同时存在。所有30岁以上的个体都表现出ADNC。27%的病例观察到α-突触核蛋白病理改变，而与年龄相关的tau星形胶质细胞病（ARTAG）、HS和边缘型为主的年龄相关TDP-43脑病神经病理改变（LATE-NC）很少见。CVD约占60%，50岁后CAA几乎普遍存在（98%），18%有BGM。即使在没有ADNC的年轻个体中，脑重量也始终低于第25百分位数。
结论
DS显示出具有早期Aβ沉积的独特神经退行性轨迹。CAA、小动脉硬化、BGM和α-突触核蛋白病理改变高度普遍，而ARTAG和LATE-NC很少观察到。
