Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA.
Department of Pathology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Neuropathol Appl Neurobiol. 2024 Oct;50(5):e13009. doi: 10.1111/nan.13009.
Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort.
Clinical variants were diagnosed antemortem, and brain tissue was collected post-mortem. Typical AD (n = 10), behavioural/dysexecutive AD (n = 6), posterior cortical atrophy (PCA) AD (n = 3), and controls (n = 10) were neuropathologically assessed for AD neuropathology, concurrent pathology including Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and vascular pathology. For quantitative assessment, we analysed the corticolimbic distribution of phosphorylated tau, amyloid-β, CD68, MHC-II, C4b, and glial fibrillary acidic protein (GFAP) using digital pathology.
Phosphorylated tau was distinctly distributed in each variant. In all variants, amyloid-β was neocortical-dominant, with a notable increase in the middle frontal cortex of behavioural/dysexecutive AD. Typical AD and PCA AD had no concurrent Lewy body disease, whereas three out of six cases with behavioural/dysexecutive AD did. LATE-NC stage >0 was observed in three AD cases, two typical AD (stage 1/3), and one behavioural/dysexecutive AD (stage 2/3). Vascular pathology was present in each variant. In typical AD, CD68 and MHC-II were hippocampal-dominant. In behavioural/dysexecutive AD, C4b was elevated in the middle frontal and inferior parietal cortex. In PCA AD, MHC-II was increased in the fusiform gyrus, and GFAP in parietal cortices. Correlations between AD neuropathology and neuroinflammation were distinct within variants.
Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.
尽管在阿尔茨海默病（AD）（非）遗忘型临床变异中，对 tau 和淀粉样蛋白-β 的神经解剖分布已有深入研究，但神经炎症的分布仍未得到探索。我们在一个临床定义明确的前瞻性 AD 队列中研究了激活的髓样细胞、星形胶质细胞和补体与淀粉样蛋白-β和磷酸化 tau 的神经解剖分布。
临床变异在生前诊断，死后收集脑组织。典型 AD（n=10）、行为/执行功能障碍 AD（n=6）、后皮质萎缩（PCA）AD（n=3）和对照组（n=10）进行 AD 神经病理学评估，包括路易体病、边缘为主的与年龄相关的 TDP-43 脑蛋白病改变（LATE-NC）、血管病理学等并发病理。为了进行定量评估，我们使用数字病理学分析了磷酸化 tau、淀粉样蛋白-β、CD68、MHC-II、C4b 和胶质纤维酸性蛋白（GFAP）在皮质边缘的分布。
磷酸化 tau 在每种变异中都有明显的分布。在所有变异中，淀粉样蛋白-β都是皮质优势，行为/执行功能障碍 AD 的中额皮质显著增加。典型 AD 和 PCA AD 没有并发路易体病，而行为/执行功能障碍 AD 中有 3 例存在。3 例 AD 病例观察到 LATE-NC 分期>0，2 例典型 AD（分期 1/3）和 1 例行为/执行功能障碍 AD（分期 2/3）。每个变异都存在血管病理学。在典型 AD 中，CD68 和 MHC-II 以海马为主。在行为/执行功能障碍 AD 中，C4b 在中额和下顶叶皮质升高。在 PCA AD 中，MHC-II 在梭状回增加，GFAP 在顶叶皮质增加。AD 神经病理学与神经炎症之间的相关性在各变异中各不相同。
我们的数据表明，神经炎症的不同参与可能增加 AD 的临床异质性，这对神经炎症为基础的生物标志物和未来的治疗有影响。
