Institute of Neuroscience and Psychology, Queen Elizabeth University Hospital Glasgow, University of Glasgow, Glasgow, UK.
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Eur J Neurol. 2021 Jan;28(1):220-228. doi: 10.1111/ene.14534. Epub 2020 Oct 13.
Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression.
Twenty-two subjects with CADASIL [50% female, 50 (±11) years] from 19 pedigrees were included in a longitudinal multimodality study using brain magnetic resonance imaging (MRI), clinical measures, neuropsychology and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO respiratory challenge.
Over 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (±4.5) ml/100 g/min over 2 years. CBF and carotid-femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow-up. Carotid intima-media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory.
Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over 2 years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor.
NOTCH3 基因突变可导致伴有皮质下梗死和白质脑病的脑常染色体显性动脉病（CADASIL），这是一种以卒中、偏头痛和痴呆为特征的脑小血管病。该疾病表现出明显的表型变异性，但无法完全解释。动物模型已显示血管功能存在早期异常。我们推测，研究血管功能的变化可能有助于深入了解疾病的进展。
我们纳入了 19 个家系的 22 例 CADASIL 患者（50%为女性，年龄 50（±11）岁），进行了一项纵向多模态研究，使用了脑磁共振成像（MRI）、临床评估、神经心理学和外周血管功能测量。MRI 研究包括结构性脑改变、脑血流（CBF）和脑血管反应性的测量，采用动脉自旋标记和 CO 呼吸挑战。
在 2 年的随访中，5 例（23%）患者发生新的卒中和短暂性脑缺血发作（TIA），1 例（5%）患者出现新的显著残疾。腔隙数量、皮质下高信号容积和微出血增加，脑容积减少。2 年内 CBF 下降了 3.2（±4.5）ml/100g/min。基线时的 CBF 和颈总动脉-股动脉脉搏波速度预测了随访时皮质下高信号容积的变化。颈动脉内膜中层厚度和年龄预测了脑萎缩。在注意力和工作记忆下降的患者中，基线 CBF 更低。
脑血流预测了高信号的影像学进展，因此是 CADASIL 疾病进展的潜在生物标志物。在 2 年的随访中，有几个相关的影像学生物标志物（CBF、脑容积、腔隙、微出血和高信号容积）发生了变化。未来的 CADASIL 研究应考虑将 CBF 评估作为预后因素。
