Alzheimer's disease and cerebral small vessel disease are the two leading causes of cognitive decline and dementia and coexist in most memory clinic patients. White matter damage as assessed by diffusion MRI is a key feature in both Alzheimer's and cerebral small vessel disease. However, disease-specific biomarkers of white matter alterations are missing. Recent advances in diffusion MRI operating on the fixel level (fibre population within a voxel) promise to advance our understanding of disease-related white matter alterations. Fixel-based analysis allows derivation of measures of both white matter microstructure, measured by fibre density, and macrostructure, measured by fibre-bundle cross-section. Here, we evaluated the capacity of these state-of-the-art fixel metrics to disentangle the effects of cerebral small vessel disease and Alzheimer's disease on white matter integrity. We included three independent samples (total n = 387) covering genetically defined cerebral small vessel disease and age-matched controls, the full spectrum of biomarker-confirmed Alzheimer's disease including amyloid- and tau-PET negative controls and a validation sample with presumed mixed pathology. In this cross-sectional analysis, we performed group comparisons between patients and controls and assessed associations between fixel metrics within main white matter tracts and imaging hallmarks of cerebral small vessel disease (white matter hyperintensity volume, lacune and cerebral microbleed count) and Alzheimer's disease (amyloid- and tau-PET), age and a measure of neurodegeneration (brain volume). Our results showed that (i) fibre density was reduced in genetically defined cerebral small vessel disease and strongly associated with cerebral small vessel disease imaging hallmarks; (ii) fibre-bundle cross-section was mainly associated with brain volume; and (iii) both fibre density and fibre-bundle cross-section were reduced in the presence of amyloid, but not further exacerbated by abnormal tau deposition. Fixel metrics were only weakly associated with amyloid- and tau-PET. Taken together, our results in three independent samples suggest that fibre density captures the effect of cerebral small vessel disease, while fibre-bundle cross-section is largely determined by neurodegeneration. The ability of fixel-based imaging markers to capture distinct effects on white matter integrity can propel future applications in the context of precision medicine.

中文翻译：

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解开阿尔茨海默氏症和小血管病对白质纤维束的影响。

阿尔茨海默氏病和脑小血管病是认知能力下降和痴呆的两个主要原因，并且在大多数记忆诊所患者中并存。通过弥散 MRI 评估的白质损伤是阿尔茨海默病和脑小血管病的一个关键特征。然而，白质改变的疾病特异性生物标志物缺失。在固定像素水平（体素内的纤维群）操作的弥散 MRI 的最新进展有望促进我们对与疾病相关的白质改变的理解。基于 Fixel 的分析可以推导通过纤维密度测量的白质微观结构和通过纤维束横截面测量的宏观结构的测量值。这里，我们评估了这些最先进的 fixel 指标解开脑小血管病和阿尔茨海默病对白质完整性影响的能力。我们纳入了三个独立样本（总共 n = 387），涵盖基因定义的脑小血管疾病和年龄匹配的对照、生物标志物确认的阿尔茨海默氏病的全谱，包括淀粉样蛋白和 tau-PET 阴性对照以及具有假定混合病理学的验证样本. 在这项横断面分析中，我们对患者和对照组进行了分组比较，并评估了主要白质束内固定指标与脑小血管病（白质高信号体积、腔隙和脑微出血计数）和阿尔茨海默病的影像学特征之间的关联。淀粉样蛋白和 tau-PET），年龄和神经变性（脑容量）的量度。我们的结果表明，（i）遗传定义的脑小血管病的纤维密度降低，并且与脑小血管病的影像学特征密切相关；(ii) 纤维束横截面主要与脑容量相关；(iii) 在存在淀粉样蛋白的情况下，纤维密度和纤维束横截面均降低，但不会因异常的 tau 沉积而进一步恶化。Fixel 指标仅与淀粉样蛋白和 tau-PET 微弱相关。综上所述，我们在三个独立样本中的结果表明，纤维密度反映了脑小血管疾病的影响，而纤维束横截面主要由神经变性决定。