IntroductionMultimodal evidence indicates Alzheimer’s disease (AD) is characterized by early white matter (WM) changes that precede overt cognitive impairment. WM changes have overwhelmingly been investigated in typical, amnestic mild cognitive impairment and AD; fewer studies have addressed WM change in atypical, non-amnestic syndromes. We hypothesized each non-amnestic AD syndrome would exhibit WM differences from amnestic and other non-amnestic syndromes.Materials and methodsParticipants included 45 cognitively normal (CN) individuals; 41 amnestic AD patients; and 67 patients with non-amnestic AD syndromes including logopenic-variant primary progressive aphasia (lvPPA, n = 32), posterior cortical atrophy (PCA, n = 17), behavioral variant AD (bvAD, n = 10), and corticobasal syndrome (CBS, n = 8). All had T1-weighted MRI and 30-direction diffusion-weighted imaging (DWI). We performed whole-brain deterministic tractography between 148 cortical and subcortical regions; connection strength was quantified by tractwise mean generalized fractional anisotropy. Regression models assessed effects of group and phenotype as well as associations with grey matter volume. Topological analyses assessed differences in persistent homology (numbers of graph components and cycles). Additionally, we tested associations of topological metrics with global cognition, disease duration, and DWI microstructural metrics.ResultsBoth amnestic and non-amnestic patients exhibited lower WM connection strength than CN participants in corpus callosum, cingulum, and inferior and superior longitudinal fasciculi. Overall, non-amnestic patients had more WM disease than amnestic patients. LvPPA patients had left-lateralized WM degeneration; PCA patients had reductions in connections to bilateral posterior parietal, occipital, and temporal areas. Topological analysis showed the non-amnestic but not the amnestic group had more connected components than controls, indicating persistently lower connectivity. Longer disease duration and cognitive impairment were associated with more connected components and fewer cycles in individuals’ brain graphs.DiscussionWe have previously reported syndromic differences in GM degeneration and tau accumulation between AD syndromes; here we find corresponding differences in WM tracts connecting syndrome-specific epicenters. Determining the reasons for selective WM degeneration in non-amnestic AD is a research priority that will require integration of knowledge from neuroimaging, biomarker, autopsy, and functional genetic studies. Furthermore, longitudinal studies to determine the chronology of WM vs. GM degeneration will be key to assessing evidence for WM-mediated tau spread.

中文翻译：

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非遗忘性阿尔茨海默病与遗忘性阿尔茨海默病相比，白质变性更大，结构连接性更低

简介多模态证据表明阿尔茨海默病 (AD) 的特点是早期白质 (WM) 变化，先于明显的认知障碍。 WM 变化绝大多数在典型的遗忘性轻度认知障碍和 AD 中进行了研究；很少有研究涉及非典型、非遗忘综合征中 WM 的变化。我们假设每种非遗忘性 AD 综合征都会表现出与遗忘性和其他非遗忘性综合征不同的 WM。 材料和方法 参与者包括 45 名认知正常 (CN) 个体； 41名失忆的AD患者； 67 名患有非遗忘性 AD 综合征的患者，包括语言减少变异型原发性进行性失语症 (lvPPA，n= 32），后皮质萎缩（PCA，n= 17), 行为变异 AD (bvAD,n= 10）和皮质基底综合征（CBS，n= 8）。所有患者均进行了 T1 加权 MRI 和 30 方向弥散加权成像 (DWI)。我们对 148 个皮质和皮质下区域进行了全脑确定性纤维束成像；连接强度通过纵向平均广义分数各向异性来量化。回归模型评估了群体和表型的影响以及与灰质体积的关联。拓扑分析评估了持久同源性（图组件和周期的数量）的差异。此外，我们还测试了拓扑指标与整体认知、疾病持续时间和 DWI 微观结构指标的关联。结果 失忆症和非失忆症患者在胼胝体、扣带回、下纵束和上纵束方面表现出比 CN 参与者更低的 WM 连接强度。总体而言，非健忘症患者比健忘症患者患有更多 WM 疾病。 LvPPA 患者患有左侧 WM 变性； PCA 患者与双侧后顶叶、枕叶和颞叶区域的连接减少。拓扑分析显示，非遗忘组而非遗忘组比对照组具有更多的连接组件，表明连接性持续较低。较长的病程和认知障碍与个体脑图中更多的连接成分和更少的周期相关。讨论我们之前报道过 AD 综合征之间 GM 变性和 tau 积累的综合征差异；在这里，我们发现连接特定综合征震中的 WM 束存在相应差异。确定非遗忘性 AD 中选择性 WM 变性的原因是一个研究重点，需要整合神经影像学、生物标志物、尸检和功能遗传学研究的知识。此外，确定 WM 与 GM 变性的时间顺序的纵向研究将是评估 WM 介导的 tau 扩散证据的关键。