Cortical microstructural correlates of astrocytosis in autosomal dominant Alzheimer disease

Objective To study the macrostructural and microstructural MRI
correlates of brain astrocytosis, measured
with 11C-deuterium-L-deprenyl (11C-DED)–PET, in familial
autosomal dominant Alzheimer disease (ADAD). Methods 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 11C-DED-PET. Results Vertex-wise interaction
analyses revealed a differential relationship between carriers and
noncarriers in the association between 11C-DED binding and
estimated years to onset (EYO) and between cortical mean diffusivity (MD)
and EYO. These differences were due to higher 11C-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, 11C-DED binding
was negatively correlated with cortical MD and positively correlated with
cortical thickness. Conclusions 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.

目的 旨在研究家族性常染色体显性阿尔茨海默病（ADAD）中，通过11C-氘代-L-司来吉兰（11C-DED）正电子发射断层扫描（PET）测量的脑星形胶质细胞增生与宏观结构及微观结构磁共振成像（MRI）的相关性。方法 总样本（n=31）纳入ADAD突变携带者（症状前10例，年龄39.2±10.6岁；症状性3例，年龄55.5±2.0岁）及非携带者（18例，年龄44.0±13.7岁），均来自携带早老素-1或淀粉样前体蛋白基因突变的家族。所有参与者均接受结构及扩散MRI检查与神经心理学评估，其中20例（6例症状前突变携带者、3例症状性突变携带者及11例非携带者）同时接受11C-DED-PET检查。结果 顶点水平交互分析揭示，突变携带者与非携带者之间，11C-DED结合率与估计发病年限（EYO）的关联、以及皮质平均扩散系数（MD）与EYO的关联均存在差异。这些差异表现为：与非携带者相比，症状前携带者的11C-DED结合率更高，而症状性携带者更低；症状前携带者的皮质MD更低，而症状性携带者更高。通过顶点水平局部相关方法发现，11C-DED结合率与皮质MD呈负相关，与皮质厚度呈正相关。结论 本概念验证研究首次证实，微观结构与宏观结构改变可反映阿尔茨海默病（AD）早期潜在的神经炎症机制。研究结果支持神经炎症在AD发病机制中的作用，对临床试验中神经影像生物标志物作为替代终点的正确解读具有潜在意义。