Pivtoraiko Violetta N, Racic Tamara, Abrahamson Eric E, Villemagne Victor L, Handen Benjamin L, Lott Ira T, Head Elizabeth, Ikonomovic Milos D
Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, United States.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Aging Neurosci. 2021 Aug 13;13:728739. doi: 10.3389/fnagi.2021.728739. eCollection 2021.
Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer's disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and -terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43-63 years and 17 late-onset AD cases aged 62-99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.
与散发性晚发性阿尔茨海默病（AD）患者相比，唐氏综合征（DS）患者具有β淀粉样蛋白（Aβ）过量产生的遗传易感性，且Aβ沉积发病更早。匹兹堡化合物B（PiB）正电子发射断层扫描（PET）可检测DS和AD患者活体中的纤维状Aβ病理，但对其与淀粉样沉积物中聚集的异质性Aβ形式之间的关系尚不清楚。我们对18例年龄在43 - 63岁的DS病例和17例年龄在62 - 99岁的晚发性AD病例的死后额叶皮质和楔前叶样本进行了定量H-PiB结合测定以及纤维状（不溶性）未修饰Aβ40和Aβ42形式以及N端截短和焦谷氨酸修饰的AβNpE3-40和AβNpE3-42形式的酶联免疫吸附测定。两个诊断组均频繁出现新皮质神经炎性斑块，而DS组的血管淀粉样病理（脑淀粉样血管病，CAA）更严重。与AD组相比，DS组的Aβ40和AβNpE3-40水平更高，而两组的Aβ42和AβNpE3-42水平无差异。这导致DS组的Aβ42/Aβ40和AβNpE3-42/AβNpE3-40比值低于AD组。在DS病例中，Aβ42/Aβ40和AβNpE3-42/AβNpE3-40比值与CAA严重程度的相关性很强，而在AD病例中则较弱。在两个诊断组中，焦谷氨酸修饰的Aβ水平均低于未修饰的Aβ水平，但DS组中两种焦谷氨酸修饰的Aβ形式相对于两种未修饰的Aβ形式的组内比例更低，而AD组则不然。两个诊断组的H-PiB结合水平无差异。这些结果表明，与晚发性AD病例相比，新皮质神经炎性斑块严重程度相似且CAA病理更严重的成年DS个体中，焦谷氨酸修饰的AβNpE3-40和未修饰的Aβ40形式占优势。尽管DS病例中Aβ形式的分子特征不同且血管淀粉样变性更严重，但皮质H-PiB结合无法区分处于淀粉样斑块病理晚期的诊断组。这突出了开发CAA选择性PET放射性药物以检测和追踪DS个体中脑血管淀粉样沉积物与Aβ斑块相关进展的必要性。
