Boston University Alzheimer's Disease Research Center, Boston University CTE Center, Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
Banner Alzheimer's Institute, Arizona State University, and Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
Eur J Nucl Med Mol Imaging. 2023 Jan;50(2):435-452. doi: 10.1007/s00259-022-05963-x. Epub 2022 Sep 24.
PURPOSE: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. METHODS: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). RESULTS: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. CONCLUSIONS: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
目的：氟-18-氟托卡比林 tau 正电子发射断层扫描（PET）用于检测阿尔茨海默病。人类影像学研究已开始研究其在慢性创伤性脑病（CTE）中的应用。需要对 CTE 中氟托卡比林-PET 与尸检的相关性进行氟托卡比林-PET 与尸检的相关性研究，以进行诊断验证。我们研究了六位前美国橄榄球运动员临终前氟托卡比林 PET 与死后 CTE 相关 tau 的神经病理学测量之间的关联。
方法：三位前国家橄榄球联盟球员和三位前大学橄榄球球员参加了 DIAGNOSE CTE 研究项目，他们去世并同意捐献大脑。六位参与者在去世前接受了氟托卡比林（tau）和氟贝他比（淀粉样蛋白）PET。所有已故参与者的大脑都接受了 CTE 的神经病理学评估。平均而言，参与者在 PET 时的年龄为 59.0（SD=9.32）岁。PET 扫描在他们去世前 20.33（SD=13.08）个月进行。使用 Spearman 相关分析，我们比较了氟托卡比林标准摄取比值（SUVR）与预先选择的复合皮质、复合边缘和丘脑 ROI 中基于数字幻灯片的 AT8 磷酸化 tau（p-tau）密度。
结果：四位脑供体均经尸检证实为 CTE，均为高期疾病（n=3 期 III，n=1 期 IV）。这四位中有三位符合 CTE 的临床综合征（创伤性脑病综合征，TES）标准。其中两位没有 CTE 尸检，其中一位符合 TES 标准。在非 CTE 病例中只有一位（路易体）和 CTE 病例中有一位（运动神经元疾病）存在伴随病理。在复合皮质（ρ=0.71）和边缘（ρ=0.77）ROI 中，氟托卡比林 SUVR 与 p-tau 密度之间存在很强的相关性。尽管丘脑 ROI 中的相关性很强（ρ=0.83），但这是一个已知存在脱靶结合的区域。SUVRS 适中，CTE 和非 CTE 病例的 SUVRS 重叠，一些区域的 p-tau 密度不一致。
结论：氟托卡比林-PET 可能有助于检测高期 CTE 神经病理学，但对 CTE p-tau 的特异性尚不确定。海马体和丘脑的脱靶氟托卡比林结合使这些关联的解释复杂化。需要能够在整个疾病过程中检测到 CTE 特定 p-tau 的体内生物标志物。
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