From the Memory Unit, Department of Neurology (E.V., V.M., A.L., J.F.), Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED (E.V., V.M., A.L., J.F.), Madrid, Spain; Department of Neurobiology (E.R.-V., D.F., O.A., E.W., A.N.), Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, and Division of Neurogeriatrics (C.G.), Karolinska Institutet, Stockholm Department of Psychology (O.A.), Stockholm University; The Aging Brain Unit (O.A., A.N.) and Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Stockholm; Department of Surgical Sciences, Section of Nuclear Medicine & PET (A.W.), Uppsala University, Sweden; and Department of Neuroimaging (E.W.), Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, United Kingdom.
Neurology. 2020 May 12;94(19):e2026-e2036. doi: 10.1212/WNL.0000000000009405. Epub 2020 Apr 14.
To study the macrostructural and microstructural MRI correlates of brain astrocytosis, measured with C-deuterium-L-deprenyl (C-DED)-PET, in familial autosomal-dominant Alzheimer disease (ADAD).
The total sample (n = 31) comprised ADAD mutation carriers (n = 10 presymptomatic, 39.2 ± 10.6 years old; n = 3 symptomatic, 55.5 ± 2.0 years old) and noncarriers (n = 18, 44.0 ± 13.7 years old) belonging to families with mutations in either the presenilin-1 or amyloid precursor protein genes. All participants underwent structural and diffusion MRI and neuropsychological assessment, and 20 participants (6 presymptomatic and 3 symptomatic mutation carriers and 11 noncarriers) also underwent C-DED-PET.
Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.
Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.
研究 C-氘-L-Deprenyl（C-DED）-PET 测量的脑星形胶质细胞的宏观和微观结构 MRI 相关性，在家族性常染色体显性阿尔茨海默病（ADAD）中。
总样本（n = 31）包括 ADAD 突变携带者（n = 10 例无症状，39.2 ± 10.6 岁；n = 3 例有症状，55.5 ± 2.0 岁）和非携带者（n = 18，44.0 ± 13.7 岁），这些家庭的突变分别位于早老素-1 或淀粉样前体蛋白基因中。所有参与者均接受了结构和弥散 MRI 以及神经心理学评估，20 名参与者（6 名无症状和 3 名有症状的突变携带者以及 11 名非携带者）还接受了 C-DED-PET。
顶点交互分析显示，在 C-DED 结合与预计发病年限（EYO）之间以及皮质平均扩散系数（MD）与 EYO 之间，携带者和非携带者之间存在差异。这些差异是由于无症状携带者的 C-DED 结合较高，而有症状携带者的结合较低，与非携带者相比，无症状携带者的皮质 MD 较低，而有症状携带者的 MD 较高。使用顶点局部相关方法，C-DED 结合与皮质 MD 呈负相关，与皮质厚度呈正相关。
我们的概念验证研究首次表明，微观和宏观结构的变化可以反映阿尔茨海默病（AD）早期潜在的神经炎症机制。这些发现支持神经炎症在 AD 发病机制中的作用，这可能对正确解释神经影像学生物标志物作为临床试验中的替代终点具有重要意义。
